Carbohydrate, Protein and Lipid

36
Metabolism
Smita Kaushik

• GLUT 4: insulin-dependent glucose uptake is

1 Carbohydrate Metabolism present in adipose tissue, the heart and skeletal
Carbohydrates are the chief components of diet (50– muscle.
60% of energy per day must come from them). They
• GLUT 5: fructose transporter is present in the
include polysaccharides (starch, glycogen, cellulose,
small intestine, the testes and sperm.
etc.), disaccharides (sucrose, lactose, maltose, etc.)
• SGLT 1: sodium-dependent glucose cotransporter
and monosaccharides (glucose, fructose, galactose,
is a symport system common to sodium and
etc.). After digestion, monosaccharides are absorbed
glucose, which is present in the small intestine and
from the intestine into circulation and transported to
the kidneys. Na+-K+ ATPase pump maintains
all the cells of body. Glucose is the main carbohydrate
intracellular sodium ion concentration
involved in cellular energy production. It is central to
all of metabolism. It is the universal fuel and source of
carbon for synthesis of most of the other compounds 1.1 Glycolysis (EMP Pathway)
(both carbohydrate and noncarbohydrate). Other EMP is an abbreviation for the names of the scientists
monosaccharides can be converted into glucose and who discovered glycolysis: Embden–Meyerhof–
have the same fate. Parnas. It is a major pathway for glucose oxidation
It reaches inside the cell through specific GLUcose and provides energy as adenosine triphosphate (ATP)
Transport (GLUT) and the cholesterol is phosphory- to the cells. It occurs in the cytoplasm of all cells.
lated (addition of phosphate group) with help of an There are two types:
enzyme, hexokinase, to form glucose-6-phosphate. • Aerobic (in the presence of oxygen and the part of
This activated glucose molecule can enter a number oxidation occurring inside the mitochondria).
of pathways: • Anaerobic (in the absence of oxygen and/or
• glycolysis mitochondria).
• hexose monophosphate pathway (HMP) shunt Aerobic glycolysis leads to the production of pyr-
• glycogen synthesis uvate, which can enter the Krebs cycle or tricarboxylic
These three pathways are common to all cells of acid (TCA) cycle. Intermediates of these pathways are
the body. used for the synthesis of various amino acids and fats.
Different glucose transporters (GLUT 1–GLUT 5) The total number of ATPs formed is eight.
are present on different tissues: • Anaerobic glycolysis produces lactate. Two ATP
• GLUT 1: insulin-independent transport across molecules are formed.
cells is seen in red blood cells (RBCs), the brain, • The main enzymes of glycolysis are:
the kidneys, the colon and the placenta. It has high
◦ hexokinase/glucokinase (only in the liver)
affinity.
◦ phosphofructokinase-1
• GLUT 2: insulin-independent transport is present
◦ pyruvate kinase
in the liver, pancreatic β-cells, the small intestine
and the kidneys. It has low affinity. • These are regulatory enzymes and catalyse
• GLUT 3: insulin-independent transport is present irreversible reactions of the pathway.
in neurons, the placenta, the kidneys and the • Enolase enzyme is inhibited by fluoride ions. It is
testes. It has high affinity. used as an anticoagulant along with potassium

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 Smita Kaushik

oxalate during collection of blood samples for • Complete oxidation of acetyl-CoA to carbon
glucose estimation, and it inhibits glycolysis. It is dioxide and water occurs along with generation of
also used in toothpaste as an anticavity agent (it a lot of energy as ATP (10 ATPs) for every
inhibits glycolysis in cavity-causing bacteria). pyruvate entering as acetyl-CoA. So, for every
• In RBCs, ATP production is bypassed to form an glucose molecule completely oxidised to carbon
important compound, 2,3-bisphosphoglycerate dioxide and water, 32 ATPs are synthesised.
(2,3-BPG), known as the Rapoport-Luebering • Intermediates of the Krebs cycle take part in
cycle. 2,3-BPG has an important role to play in gluconeogenesis, transamination (the conversion
oxygen dissociation from haemoglobin (Hb) at of one amino acid into another), fatty acid
a cellular level. 2,3-BPG levels increase at high synthesis, haem synthesis, cholesterol and steroid
altitude, in pulmonary hypoxia and anaemic synthesis.
conditions so that tissue oxygenation is improved • Concentration of oxaloacetate (OAA), an
(by increasing dissociation of oxygen from Hb in intermediate, is the most important limiting factor
cells). for continuation of the cycle; also concentrations
• RBCs, the lens of the eye, the retina, the renal of nicotinamide adenine dinucleotide hydrogen
cortex and the brain exclusively use only glucose (NADH) and/or ATP in the cell.
for energy production. During prolonged
starvation the brain switches over to ketone bodies
as an energy source so these other tissues can use
1.3 Glycogen Metabolism
glucose. • Glycogen (homopolysaccharide) is the storage
• Regulation: insulin activates the regulatory form of glucose in all cells. The liver and skeletal
enzymes to increase the rate of glycolysis. muscles have the maximum amount.
Glucagon inhibits glycolysis by inhibiting these • Glycogen synthesis (glycogenesis) is a process
enzymes. requiring energy (ATP), starting with glucose-
• Lactic acidosis occurs under anaerobic or hypoxic 6-phosphate with more glucose units binding in
conditions like strenuous muscular activity. a head-to-tail fashion. It is a highly branched
Lactate accumulates in skeletal muscles, causing structure. The enzyme is glycogen synthase and is
cramps and pain. It can also occur with deficiency a branching enzyme (introducing branch points
of the enzyme, pyruvate kinase, or in thiamine after every 5–6 glucosyl units). The donor of
(vitamin B1) deficiency. glucose units is UDP-glucose.
• Pyruvate synthesised in aerobic glycolysis enters • Glycogen breakdown (glycogenolysis) occurs in
the mitochondria for further oxidation via the a fasting state when energy is required quickly.
Krebs cycle. The enzyme glycogen phosphorylase removes one
glucose unit at a time as glucose 1-phosphate from
the ends of glycogen chains. A debranching
1.2 The Krebs Cycle (TCA Cycle) enzyme removes glucose residue from each
• The Krebs cycle or tricarboxylic acid cycle branch point.
occurs in the mitochondria, and is an • Liver glycogen serves as a source of blood glucose:
amphibolic pathway (both oxidative and this maintains blood glucose levels due to the liver
synthetic processes occur). It is the final having an enzyme called glucose-6-phosphatase,
common pathway for oxidation of which converts into glucose.
carbohydrates, lipids and proteins: glucose, • Muscle glycogen, on breakdown, forms lactate and
fatty acids and many amino acids are provides energy to the muscle only: it cannot
metabolised to acetyl-coenzyme A (CoA) or contribute to blood glucose. Glucose-
intermediates of the Krebs cycle. 6-phosphatase is absent in muscle, so glucose
• Pyruvate from glycolysis enters the Krebs cycle cannot be formed.
after conversion to acetyl-CoA with the help of the • In the liver, glycogenesis is promoted by a high
enzyme pyruvate dehydrogenase (PDH: insulin:glucagon ratio (fed state) and
a multienzyme complex dependent on vitamin glycogenolysis is promoted by a low insulin:
B complex for its activity). glucagon ratio (starvation).
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 Carbohydrate, Protein and Lipid Metabolism

• Under stress conditions, epinephrine acts on the

muscle and liver to promote glycogen breakdown.
1.5 Hexose Monophosphate Pathway
• Cyclic AMP (cAMP) integrates regulation of • The hexose monophosphate pathway (HMP) is an
glycogen breakdown and synthesis in a reciprocal alternative route for glucose metabolism, with no
manner by promoting activation of phosphorylase energy production.
and inhibiting glycogen synthase. • HMP produces nicotinamide adenine dinucleotide
• In utero, the fetus receives a constant supply of phosphate (NADPH) and ribose (a pentose sugar):
glucose through the placenta. fetal tissues NADPH is utilised for reductive biosynthesis: the
function in an environment dominated by synthesis of fatty acids, cholesterol and other
insulin, which promotes fetal growth. This also steroid compounds. Ribose sugar (a pentose) is
leads to increased glycogen synthesis and storage. used for nucleotide and nucleic acid biosynthesis.
At birth, when the cord is clamped, maternal • The main enzyme is glucose-6-phosphate
glucose supply cuts off abruptly and release of the dehydrogenase (G6PD).
counterregulatory hormones, glucagon and • Deficiency of G6PD causes haemolytic anaemia
epinephrine, occurs to maintain the blood (due to the nongeneration of NADPH, which is
glucose levels of newborn. required to maintain RBC membrane integrity).
• The inability to maintain blood glucose after birth G6PD deficiency does not affect ribose production.
could be due to maternal malnutrition (the fetus did • The HMP pathway is especially active in tissues
not receive enough glucose in the antenatal period), where reductive biosynthesis occurs such as the
inborn error of glycogen metabolism (glycogen liver, adipose tissue, adrenal cortex, thyroid gland,
storage diseases) or gluconeogenesis and the inability RBCs, testes and lactating mammary glands.
to oxidise fatty acids for energy production. • All cells synthesise ribose sugar.
• Glycogen storage diseases (GSD) occur due to
inherited deficiencies in specific enzymes of 1.6 Hexose Metabolism
glycogen metabolism in both the liver and muscle.
See Table 36.1. 1.6.1 Fructose
• High dietary fructose (sucrose and high fructose
1.4 Gluconeogenesis syrups) is rapidly absorbed from the intestine,
• Gluconeogenesis is the pathway for the synthesis taken up by liver cells and undergoes glycolysis
of glucose from noncarbohydrate sources such as (faster than glucose). This occurs because fructose
lactate, glycerol and some amino acids like alanine bypasses the phosphofructokinase regulatory step
(glucogenic amino acids) and propionyl-CoA. It in glycolysis, thus flooding the lipogenic pathways,
occurs in the liver and kidney. Except for three causing increased fatty acid synthesis and their
regulatory steps, it is a reversal of glycolysis. It is esterification to triacylglycerols in adipose tissues.
an energy requiring process; the source of ATP is • Deficiency of fructokinase causes essential
fatty acid oxidation. fructosuria, a rare and benign condition.
• Cori’s cycle: the conversion of lactate (generated • Deficiency of hepatic aldolase B causes hereditary
in skeletal muscles during anaerobic glycolysis) fructose intolerance (high levels of fructose-
into glucose; occurs in the liver and kidneys. 1-phosphate) and hypoglycaemia. It can be fatal if
• Glucagon and epinephrine stimulate not treated.
gluconeogenesis by activating the key enzymes:
1.6.2 Galactose
◦ Pyruvate carboxylase (pyruvate →
oxaloacetate); inside the mitochondria • Galactose can be synthesised in the body from
◦ Phosphoenolpyruvate carboxykinase: (OAA → glucose by the enzyme 4-epimerase.
phosphoenolpyruvate); in the cytoplasm • Galactose is required in the body as a constituent
◦ Fructose-1,6-bisphosphatase (fructose- of glycolipids (cerebrosides), glycoproteins,
1,6-bisphosphate → fructose-6-phosphate) proteoglycans and in lactating mammary glands.
◦ Glucose-6-phosphatase (glucose 6-phosphate • Dietary galactose is not essential for lactose
→ glucose) synthesis during lactation.
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 Table 36.1 Glycogen storage diseases

Type Defective enzyme Organ affected Glycogen in the affected organ Clinical features
I Von Gierke G-6-ptase or transport system Liver and kidney Increased amount; normal structure Massive enlargement of the liver. Failure to
thrive. Severe hypoglycaemia, ketosis,
hyperuricemia, hyperlipaemia.
II Pompe α-1,4-glucosidase (lysosomal) All organs Massive increase in amount; normal Cardiorespiratory failure causes death; usually
structure before age 2.

[Link] [Link]
III Cori Amylo-1,6-glucosidase (debranching Muscle and liver Increased amount; short outer Like type I, but milder course.
enzyme) branches
IV Andersen Branching enzyme (α-1,4 → α-1,6) Liver and spleen Normal amount; very long outer Progressive cirrhosis of the liver. Liver failure
branches causes death, usually before age 2.
V McArdle Phosphorylase Muscle Moderately increased amount; normal Limited ability to perform strenuous exercise
structure because of painful muscle cramps.
Otherwise, patient is normal and well
developed.
VI Hers Phosphorylase Liver Increased amount Like type I, but a milder course.
VII Phosphofructokinase Muscle Increased amount; normal structure Like type V.
VIII Phosphorylase kinase Liver Increased amount; normal structure Mild liver enlargement. Mild hypoglycaemia.

Types I to VII are inherited as autosomal recessives. Type VIII is sex linked.
Used with permission from Berg, J. M., Tymoczko, J.L., Stryer, L. (2012). Biochemistry, 7th ed., W. H. Freeman and Company

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 Carbohydrate, Protein and Lipid Metabolism

• Defects in galactokinase, galactose 1-phosphate • Gestational DM occurs when pregnant women

uridyl transferase and/or 4-epimerase may lead to without a previous history of DM develop
galactosaemia, which is characterised by failure to high blood glucose levels after 20 weeks of
thrive, intellectual disability, liver failure and gestation.
premature cataracts. • The categories of fasting plasma glucose (FPG)
values are as follows:
1.7 Polyol Pathway ◦ FPG <100 mg/dL (5.6 mmol/L): normal fasting
• Persistent hyperglycaemia causes conversion of glucose; HbA1c <6.0%
glucose to sorbitol in tissues such as the lens, ◦ FPG 100–125 mg/dL (5.6–6.9 mmol/L): IFG
peripheral nerves and renal glomeruli. NADPH (impaired fasting glucose); HbA1c 6.0–6.4%
and aldose reductase are required for this reaction. ◦ FPG <126 mg/dL (<7.0 mmol/L): impaired
Sorbitol cannot diffuse out of cells, so it glucose tolerance; HbA1c 6.0–6.4
accumulates and causes osmotic swelling leading ◦ FPG ≥126 mg/dL (7.0 mmol/L): provisional
to cataract formation, neuropathy and diagnosis of diabetes; HbA1c >6.5
nephropathy. Sorbitol can be further converted to • The corresponding categories when the oral
fructose. glucose tolerance test (OGTT) is used are as
follows:
1.8 Diabetes Mellitus ◦ two-hour postload glucose <140 mg/dL
• Diabetes mellitus (DM) is a group of metabolic (7.8 mmol/L): normal glucose tolerance
disorders characterised by persistent ◦ two-hour postload glucose 140–199 mg/dL
hyperglycaemia, along with polyuria, polydipsia (7.8–11.1 mmol/L): impaired glucose tolerance
and polyphagia. (IGT)
• It occurs due to complete or partial deficiency of ◦ two-hour postload glucose ≥200 mg/dL
insulin. (11.1 mmol/L): provisional diagnosis of
• If left untreated, it can lead to many diabetes
complications: Used with permission from Geneva: WHO, 2006, 21.I
◦ acute complications: diabetic ketoacidosis SBN 978–92-4–159493-6
(DKA), hyperosmolar hyperglycaemic
• Diagnosis of gestational DM (GDM) is made with
coma
a 100 g or 75 g glucose load. See Table 36.2.
◦ chronic complications: neuropathies,
nephropathy, retinopathy, cardiovascular
diseases 1.9 Leptin Hormone
• Type I DM is the result of the absolute deficiency • Leptin is produced by adipose cells and helps to
of insulin. It has an early onset, also known as regulate energy balance by inhibiting hunger. Its
juvenile diabetes. DKA is a common complication deficiency can lead to obesity. Leptin acts on
in untreated and uncontrolled states. Exogenous specific receptors in the hypothalamus to inhibit
insulin supplementation is essential. Severe hunger (by counteracting the effects of
hypoglycaemia is common due to insulin overdose neuropeptide Y and anandamide) and stimulate
or missing a meal after insulin. Also known as satiety (promoting synthesis of α-melanocyte
insulin-dependent diabetes mellitus (IDDM). stimulating hormone, which is a hunger
• Type II DM is due to insulin resistance with suppressant).
hyperinsulinism. Glucose receptors on cell • In fetal lungs, leptin is induced by parathormone-
membranes do not respond to insulin for glucose related peptide (PTHrP), acts on type II
uptake. Thus, cellular starvation occurs along with pneumocytes and causes surfactant expression.
hyperglycemia. It is also known as noninsulin- • The placenta produces leptin, which inhibits
dependent diabetes mellitus (NIDDM) and has an uterine contractions.
adult onset. • Leptin is also secreted into breast milk.

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 Smita Kaushik

Table 36.2 Diagnosis of GDM with a 100 g or 75 g glucose load • The highly alkaline (due to bicarbonate ion)
pancreatic secretions released into the small
mg/dL mmol/L
intestine neutralise the acidic gastric contents, and
100 g glucose load the various proteases (as inactive zymogens) cause
Fasting 95 5.3 further breakdown of proteins.
1h 180 10.0 • Trypsinogen is cleaved to active enzyme trypsin by
2h 155 8.6 the action of a protease enteropeptidase or
3h 140 7.8 enterokinase, which is secreted from the brush-
75 g glucose load border cells of the small intestine.
Fasting 95 5.3 • Trypsin in turn causes activation of other
1h 180 10.0
proteases:
2h 155 8.6 ◦ chymotrypsinogen to chymotrypsin
◦ proelastase to elastase
Two or more of the venous plasma concentrations must be met ◦ procarboxypeptidases to carboxypeptidases
or exceeded for a positive diagnosis. The test should be done in
the morning after an overnight fast of between 8 and 14 hours • Trypsin plays a pivotal role in digestion as it
and after at least 3 days of unrestricted diet (≥150 g carbohydrate
per day) and unlimited physical activity. The subject should
breaks down dietary proteins and activates other
remain seated and should not smoke throughout the test. pancreatic digestive proteases.
Used with permission from American Diabetes Association • Trypsin, chymotrypsin and elastase are serine
(2004). Diagnosis and classification of diabetes mellitus. Diabetes proteases and act as endopeptidases. Trypsin is the
Care, 27 (suppl. 1),: s5–10
most specific; it cleaves bonds at lysine or arginine.
Chymotrypsin cleaves bonds at hydrophobic or
acidic amino acids. Elastase degrades the protein
2 Protein Metabolism elastin and bonds between small amino acids. The
smaller peptides formed by the action of these
• Dietary proteins are the primary source of enzymes are further attacked by the exopeptidases,
nitrogen in the body. Amino acids, produced by which act on the ends of peptides and break one
the digestion of dietary proteins, are absorbed
bond at a time; for example, carboxypeptidases (as
through intestinal epithelial cells and enter the
procarboxypeptidases, activated by trypsin)
circulation for assimilation. remove amino acids from the carboxyl end of the
peptide chain.
2.1 Protein Digestion and Amino Acid • Exopeptidases, aminopeptidases and intracellular
Absorption peptidases bring about further breakdown of
peptides into amino acids, which are absorbed
• Proteolytic enzymes or proteases break down into the circulation.
dietary proteins into constituent amino acids.
These enzymes are released in the stomach and
intestine as zymogens (inactive, larger forms). In
2.2 Absorption of Amino Acids
the intestinal lumen, zymogens are cleaved to • Amino acids are absorbed from the intestinal
produce the active forms. lumen and brush border by secondary active
• Chief cells secrete pepsinogen, and parietal cells sodium-ion-dependent transport, facilitated
secrete hydrochloric acid (HCl) into the stomach diffusion or through the γ- glutamyl cycle.
lumen. HCl (pH2–3) alters the conformation of • Absorbed amino acids are taken up by cells, and
pepsinogen such that it can autocleave itself, utilised for protein synthesis or other nitrogen-
forming active pepsin. containing compounds or oxidised for energy.
• Dietary proteins are denatured by the acid in the
stomach. Pepsin acts as an endopeptidase and 2.3 Protein Chemistry
cleaves peptide bonds between aromatic and
acidic amino acids. Smaller peptides and free • There are about 300 or more known amino acids
amino acids are the products of protein digestion in nature, but only 20 amino acids make proteins
that leave the stomach. in our body. These are known as standard or
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 Carbohydrate, Protein and Lipid Metabolism

Table 36.3 Essential and nonessential amino acids

Essential or semiessential Nonessential

amino acids amino acids
Phenylalanine Hydroxyalanine
Tryptophan Serine
Valine Glutamic acid
Leucine Aspartic acid
Isoleucine Proline
Lysine Pyrolysine
Figure 36.1 Amino acid structure. Source: [Link] Threonine Tyrosine
Methionine Glycine
primary amino acids. Two more amino acids have Histidine Cysteine
been added to this list: selenocysteine and Arginine Selenocysteine
pyrrolysine, which are formed in the body during
the translation process (co-translationally).
• All the mammalian amino acids are α-amino
• The eight essential amino acids are phenylalanine,
acids. They have an amino group (-NH2),
tryptophan, valine, leucine, isoleucine, lysine,
a carboxyl group (-COOH), a hydrogen atom (-H)
threonine and methionine. The two semi-essential
and a side chain (-R), bound covalently to the
amino acids are histidine and arginine. The
central α-carbon atom. All the 20 amino acids
remainder are nonessential. See Table 36.3.
differ in the side chains. See Figure 36.1.
• Glycine is the simplest amino acid, its R group
being an H-atom. 2.4 Purification of Proteins
• Valine, leucine and isoleucine are branched-chain • A mixture of proteins can be separated or purified
amino acids. These, along with alanine, contain by various techniques such as chromatography
aliphatic side chains, so are also hydrophobic in and electrophoresis.
nature. • High-pressure liquid chromatography is one of
• Phenylalanine, tyrosine and tryptophan have the most sensitive techniques for the separation of
aromatic side chains. different proteins at a faster rate and at high
• Methionine and cysteine contain a sulphur group resolution.
(-SH); cystine is a dimer of cysteine having • Protein purity is assessed by polyacrylamide gel
a disulphide bond (S-S). electrophoresis (PAGE), especially sodium
• Threonine and serine contain a hydroxyl group dodecyl sulphate (SDS) PAGE. SDS is an anionic
(-OH). detergent, which imparts an overall negative
• Glutamic acid and aspartic acid containing an extra – charge to the polypeptide chains depending on
COOH group are the acidic amino acids, glutamine their mass, such that proteins migrate on the
and asparagine being their amides respectively. polyacrylamide gel under the influence of electric
• Arginine and lysine have an extra amino group, current on the basis of their molecular weight.
hence are the basic amino acids. • Isoelectric focusing is a technique that separates
• Histidine has an imidazole group and plays an proteins depending on their isoelectric pH.
important role in the buffering action of proteins. Isoelectric pH is the pH at which the molecule or
• Proline contains an imino (-NH) group instead of ion has zero net charge. Molecules or ions bearing
an amino (-NH2) group; thus is also known as an zero net charge (i.e., having equal number
imino acid. opposite charges) are called zwitterions.
• Nutritionally, these have been divided into
essential (not synthesised in the body, so have to 2.5 Synthesis of Proteins: Translation
be taken in the diet) and nonessential (synthesised
• Translation is a process by which cells synthesise
in the body).
proteins. It occurs on ribosomes (attached to
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 Smita Kaushik

endoplasmic reticulum) and is guided by mRNA. • As one ribosome moves along the mRNA,
It is an energy consuming process (in the form of producing one polypeptide chain, a second
guanosine-5-triphosphate (GTP)). ribosome may bind to the vacant 5’-end of mRNA.
• The genetic message encoded in DNA is first Many ribosomes can simultaneously translate
transcribed into mRNA, and the nucleotide a single mRNA, forming a complex called
sequence of mRNA then determines the sequence polysome.
of constituent amino acids in a protein. • As the nascent polypeptide chain leaves the
• The portion of mRNA that specifies the amino ribosome complex, it is folded into a three-
acid sequence of a protein is read in codons. dimensional conformation, which is the native
Codons are a set of three nucleotides, which or active form of the protein. This process
specify specific amino acids. Initiation of the requires action of some proteins known as
synthesis of a polypeptide chain starts with the chaperone proteins (e.g., hsp70, hsp60 or
codon AUG, which specifies the amino acid chaperonins).
methionine. Codons on mRNA are read • Posttranslational modification of some amino acid
sequentially in the 5’ to 3’ direction, starting with residues occurs in the newly formed proteins. This
5’-AUG, which sets the reading frame, and ending includes:
with a 3’-termination (or stop) codons: UAG, ◦ formation of a disulphide bond between two
UGA or UAA. The protein is produced from its cysteine residues
N-terminus to its C-terminus. ◦ glycosylation (addition of carbohydrate
• Specific tRNA carries amino acids to the ribosomal groups)
site of protein synthesis. Base-pairing between the ◦ phosphorylation (addition of phosphate
anticodon of the tRNA and the codon on the mRNA groups)
ensures the insertion of the amino acid onto the ◦ methylation (addition of methyl groups)
growing polypeptide chain at the appropriate
◦ carboxylation (addition of carboxyl groups)
position as per the information on the DNA.
◦ hydroxylation (addition of hydroxyl groups)
• The binding of initial methionyl-tRNA
◦ cleavage of peptide bonds, and so on
(methionine attached to its specific tRNA) to
mRNA and the ribosome is called initiation and
involves certain cytoplasmic proteins called 2.6 Inhibitors of Protein Synthesis
initiation factors and GTP (the energy source). in Prokaryotes
• After initiation, sequential addition of specific
• Streptomycin: binds to the 30S prokaryotic
amino acids according to the codon sequence on
the mRNA, leads to the elongation of the ribosomal subunit and prevents initiation of
polypeptide chain. Elongation involves three steps: protein synthesis. It also causes the misreading of
mRNA and thereby disrupts the bacterial growth.
1. Addition of an aminoacyl-tRNA to a site on the • Tetracyclin: binds to the 30S subunit and inhibits
ribosome, where it binds and base-pairs with its the binding of aminoacyl-tRNA to the A-site on
next or the second codon on the mRNA. the ribosome.
2. Formation of a peptide bond between the first • Chloramphenicol: binds to the 50S subunit and
and second amino acids. inhibits peptidyltransferase.
3. Translocation: movement of mRNA relative to • Erythromycin: binds to 50S and prevents
the ribosome, so that another aminoacyl-tRNA translocation.
can bind to the third mRNA codon and to the
ribosome.
2.7 Protein Catabolism
• Termination: the above three steps are repeated
until a termination codon is reached on the • Human adults degrade 1–2% of body protein,
mRNA. Release factors bind instead of a charged mainly muscle protein, every day. Of the released
tRNA (aminoacyl-tRNA). This causes release of amino acids, 75–80% are reutilised for new
the completed polypeptide chain from the protein synthesis. The remainder are degraded
ribosome. and the nitrogen content is converted into urea.

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 Carbohydrate, Protein and Lipid Metabolism

2.8 Biosynthesis of Urea NADP+ as coenzyme. Oxidative deamination of

glutamate by hepatic GDH is the major
Urea biosynthesis divided into four stages:
pathway for production of ammonia in
• transamination mammals.
• oxidative deamination ◦ Oxidative deamination by L-amino acid
• ammonia transport oxidase is the minor pathway for ammonia
• urea cycle production. It occurs in the mammalian liver
and the kidneys.
2.8.1 Urea Cycle
3. The free ammonia consequently produced is then
The urea cycle consists of five enzymatically con- transported to the liver and kidneys in the form of
trolled steps, which are catalysed by carbamoyl phos- glutamine.
phate synthetase, ornithine transcarbamylase,
argininosuccinate synthetase, argininosuccinase and ◦ Free ammonia (NH+4) is very toxic,
arginase. especially to the central nervous system.
Normal blood levels of free ammonia are
1. Amino groups of all the released amino acids are
10–20μg/dL. An increase in its level leads to
used to form glutamate. This happens by the
hyperammonaemia. It can lead to ammonia
process of transamination.
intoxication, causing slurring of speech,
◦ In this, there is interconversion of a pair of blurred vision and tremors. The brain is
amino acids and a pair of keto acids. affected because of severe depletion of α-
◦ Enzymes required: transaminases or ketoglutarate, which impairs the function of
aminotransferases. the TCA cycle, leading to energy depletion
◦ Coenzyme: pyridoxal phosphate; the active in nervous tissues.
form of vitamin B6. ◦ As such, free ammonia is ‘trapped’ as glutamine
◦ Alanine transaminase (alanine-pyruvate by the the enzyme glutamine synthase; the
transaminase) and glutamate transaminase substrate is glutamate.
(glutamate-α ketoglutarate transaminase) are ◦ Glutamine transports ammonia to the
the most common transaminases catalysing liver and kidney, where another
transfer of amino groups from all amino enzyme glutaminase acts on it and releases
acids to form alanine and glutamate. Alanine ammonia, which is then converted to urea.
in turn transfers its amino group to 4. Urea biosynthesis: urea is the major end product
glutamate. This is important as L-glutamate of nitrogen metabolism in humans. Animals that
is the only amino acid in mammalian tissues, excrete amino nitrogen as urea are called ureotelic
which undergoes oxidative deamination at animals.
an appreciable rate.
◦ Alanine aminotransferase is also known as ◦ The urea cycle was discovered by Hans Kreb
glutamate pyruvate transaminase and aspartate (who also discovered the TCA cycle) and Kurt
aminotransferase as glutamate oxaloacetate Henseleit, so it is also known as the Krebs–
transaminase. These are important diagnostic Henseleit cycle.
enzymes and play an important role in the ◦ It involves five steps/reactions: the first two in
diagnosis of liver and cardiac diseases. the mitochondria and the next three in the
cytosol of the hepatic cells.
2. Deamination: the removal of α-amino groups
from amino acids as free ammonia of two a. Synthesis of carbamoyl phosphate: in the
types: mitochondria of hepatocytes, ammonia
(NH+4) and bicarbonate (CO2) combine
◦ Oxidative deamination: glutamate is to form carbamoyl phosphate. The
oxidatively deaminated to α-ketoglutarate and enzyme is carbamoyl phosphate
the amino group is liberated as free ammonia. synthetase I (CPSI). This is the rate-
Enzyme is glutamate dehydrogenase (GDH). limiting step for urea synthesis. See
◦ GDH is a zinc containing metallo-enzyme, Figure 36.2.
present in mitochondria. It requires NAD+ or
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 Smita Kaushik

+
leucine and other branched-chain amino acids
HCO3– NH4
(valine, leucine, isoleucine) transamination/oxidation
urea has been observed during pregnancy, increasing their
H2O
HCO3– + NH4+ availability for fetal growth. Pregnancy is also asso-
2ATP arginase arginine ciated with hypoaminoacidaemia, reflecting an
CPSI enhanced placental uptake of amino acids. Placental
2ADP + Pi ornithine arginino- fumarate uptake is an active process, using selective transpor-
succinate
lyase ters and energy.
OTC
Pi argininosuccinate
2.10 Special Products Formed
argininosuccinate
citrulline synthetase AMP + PPi from Amino Acids
aspartate ATP
1. Glycine: forms haem, creatine, purines, along with
Figure 36.2 Urea cycle. glutamate and cysteine forms glutathione, glycine
conjugates. Glycine itself acts as an inhibitory
neurotransmitter.
b. Synthesis of citrulline: carbamoyl 2. Methionine: forms S-adenosylmethionine (SAM),
phosphate combines with ornithine to polyamines (spermine, spermidine). Along with
form citrulline (enzyme: ornithine glycine and arginine, methionine forms creatine.
transcarbamoylase), which crosses the 3. Tryptophan: forms serotonin, melatonin,
mitochondrial membrane and enters the tryptamine and niacin (vitamin B5).
cytoplasm. 4. Tyrosine: forms thyroid hormone (T3, T4),
c. Synthesis of arginosuccinate: citrulline in dihydroxyphenylalanine (DOPA), epinephrine,
the cytosol then combines with aspartate to norepinephrine and melanin.
form arginosuccinate. Enzyme: 5. Glutamate: forms gamma-aminobutyric acid,
arginosuccinate synthetase. which is an inhibitory neurotransmitter.
d. Arginosuccinate then cleaves into arginine
and fumarate. Fumarate so formed enters
the TCA cycle; thus, the urea cycle is linked
2.11 Disorders of Catabolism of the
to the TCA cycle through fumarate. Amino Acid Carbon Skeleton
e. Finally, arginine cleaves to form urea and 1. Phenylketonuria: the defective enzyme,
ornithine; ornithine being utilised again phenylalanine hydroxylase, leads to
for urea synthesis. hyperphenylalaninaemia as phenylalanine cannot
5. Urea contains two amino groups: one from be converted to tyrosine. In addition, alternative
glutamine [glutamine → glutamate + free metabolites are produced: phenyl-pyruvate,
ammonia (NH4+)], and the second from aspartate. phenyl-lactate, phenyl-acetate, and so on. These
are excreted in urine, hence the name
2.8.2 Regulation of Urea Synthesis phenylketonuria. Intellectual disability occurs due
to high phenylalanine levels, and skin tone is very
• The first step catalysed by CPSI is the rate-limiting fair due to low melanin levels. Treatment is with
step. a phenylalanine-free diet until six years of age,
• Normal levels of blood urea are 2.5–7.1 nmol/L when maximum brain growth occurs.
(7–20 mg/dL). 2. Alkaptonuria: defective enzyme homogentisate
oxidase (in tyrosine catabolism). This leads to
2.9 Protein Metabolism During Pregnancy accumulation of homogentisate in tissues, causing
During pregnancy, there is a positive nitrogen balance pigmentation (ochronosis), and is excreted in the
as it is a time of growth. There is increased uptake of urine, which turns black on standing due to
amino acids for tissue growth, both maternal and oxidation of homogentisate to alkapton. It is
fetal, with a decrease in urea synthesis. A low rate of a benign condition.

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 Carbohydrate, Protein and Lipid Metabolism

3. Hartnup disease: an autosomal recessive condition, ◦ Glycerophospholipids and

with defects in intestinal and renal transport of sphingophospholipids are important
neutral amino acids including tryptophan. There is components of biomembranes, nervous tissue
neutral aminoaciduria, causing a deficiency of and lipoproteins.
tryptophan. This produces pellagra-like signs and — Glycerophospholipids are synthesised
symptoms due to decreased synthesis of niacin. from fatty acyl-CoA, which combines with
4. Maple syrup urine disease: an autosomal recessive glycerol 3-phosphate to form phosphatidic
condition with branched-chain ketonuria. The acid. Different groups are added to C-3 of
defective enzyme is α-keto acid decarboxylase, g-3-p of phosphatidic acid to produce
branched-chain amino acids and their keto acids amphipathic compounds like
elevated in blood and urine. Urine has the odour phosphatidylcholine, phosphatidylinositol
of burnt sugar or maple syrup. and cardiolipin (present in mitochondrial
5. Carcinoid syndrome: not related to amino acid membrane and the only phospholipid that
catabolism. It is a paraneoplastic syndrome due to is antigenic in nature).
carcinoid tumours. There is increased endogenous — Plasmalogens (present in cardiac muscles)
secretion of serotonin and kallikrein. Tryptophan is and platelet-activating factor are formed
diverted to serotonin synthesis, which is normally when a long-chain fatty alcohol links to
a minor pathway. Due to this, there is decreased glycerol 3-phosphate.
synthesis of niacin, leading to pellagra-like — Phospholipids are broken down by
symptoms along with the features of carcinoid phospholipases (found in pancreatic juice,
syndrome. cell membranes and lysosomes).
— Sphingolipids are predominantly present
3 Lipid Metabolism in the brain and nervous tissues. They have
sphingosine, an amino (serine) alcohol
3.1 Lipid Chemistry instead of glycerol, as the backbone to
• Lipids are a heterogenous group of compounds which acyl-CoA binds with an amide
having common properties of the following: linkage: this is called a ceramide.
— Sphingomyelin contains ceramide attached
1. Relative insolubility in water to phosphocholine or
2. Solubility in nonpolar solvents such as ether, phosphoethanolamine as the polar head
chloroform and benzene group. Sphingolipids are degraded by
• Lipids include: fatty acids and triacylglycerols lysosomal enzymes.
(TGs); glycerophospholipids and sphingolipids; — Glycolipids or glycosphingolipids contain
eicosanoids; cholesterol, bile salts and steroid ceramide, to which sugar is attached. They
hormones; fat-soluble vitamins; and are predominantly present in the brain and
lipoproteins. myelin sheath of nervous tissue. The sugar
◦ Fatty acids, stored as triacylglycerol in adipose molecule can be glucose, galactose, sialic
tissue, are an efficient source of energy for the acid, and so on. They are further divided
body. Fatty acids are saturated if they have no into cerebrosides and gangliosides:
double bonds, monounsaturated with one – cerebroside: ceramide plus a glucose or
double bond, and polyunsaturated with more galactose molecule
than one double bond. – gangliosides: ceramide plus sialic acid
— Essential fatty acids are polyunsaturated ◦ PUFAs containing 20-carbons form
fatty acids (PUFAs), which cannot be eicosanoids, which regulate many cellular
synthesised in the body: linoleic acid, processes.
linolenic acid and arachidonic acid ◦ Cholesterol regulates the fluidity of
— Omega-3 fatty acids (e.g., linolenic acid) biomembranes. It is a precursor for the
found in fish oils are cardioprotective by synthesis of bile acids (required for digestion of
inhibiting platelet aggregation. dietary fats), a precursor for the synthesis of

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 Smita Kaushik

steroid hormones and vitamin D and an

O
important constituent of lipoproteins like low-
(d’-C) CH3(CH2)13CH2 OH (carboxyl group)
density lipoprotein (LDL) and high density
lipoprotein (HDL). Figure 36.3 Structure of a saturated fatty acid with a carboxylic
◦ Fat-soluble vitamins A, D, E and K are involved acid group and a long hydrocarbon chain consisting of carbon (C)
and hydrogen (H) atoms.
in varied functions such as vision, cellular
growth, calcium metabolism, antioxidant
function and blood clotting.
◦ Lipoproteins like chylomicron (CM), very low • Coenzymes/cofactors: ATP, Mn2+, biotin, HCO3+
density lipoprotein (VLDL), LDL, and HDL are and NADPH.
the transport forms of lipids. • Substrate: cytoplasmic acetyl-CoA.
• Product: free fatty acid (palmitate is the most
3.2 Digestion and Transport common example with C-16) – see Figure 36.3.
• Fatty acid synthesis occurs in the fed state, when
of Dietary Lipids there is excess of carbohydrate. Excess dietary
• TGs are the main dietary lipids. glucose undergoes glycolysis in the cytoplasm to
• Lipid digestion starts in the mouth: lingual lipase form pyruvate, which is converted to acetyl-CoA in
(from Ebner’s glands in the tongue), then in the the mitochondria. Acetyl-CoA combines with
stomach: gastric lipase. Major digestion of lipids oxaloacetate to form citrate. Citrate is transported
occurs in the small intestine, where pancreatic lipase to the cytoplasm by its specific transporter on the
acts on dietary lipids to form free fatty acids (FFAs) inner mitochondrial membrane. In the cytoplasm,
and 2-monoacyl glycerols (2-MAG). Pancreatic citrate cleaves to form acetyl-CoA and oxaloacetate.
lipase requires action of bile salts and colipase for • In the cytoplasm, acetyl-CoA is used to synthesise
proper breakdown of lipids; bile salts cause the palmitic acid, 16-C saturated fatty acid. Acetyl-
emulsification of fats (the breaking down of fats into CoA carboxylase catalyses the rate-limiting step of
smaller droplets to allow complete action of the conversion of acetyl-CoA to malonyl CoA. Malonyl
enzyme lipase). Colipase acts as an interface between CoA provides the acetyl-CoA moiety for fatty acid
water insoluble fats and water-soluble enzymes. synthesis on FAS enzyme complex. See Figure 36.4.
• The breakdown products (FFAs and 2-MAG) are • FAS is a multifunctional polypeptide chain; that is,
taken up into the intestinal epithelial cells by a single polypeptide has multiple functional
simple diffusion, where triacylglycerols are domains, which catalyse different reactions during
reformed and transported into blood as CM, the sequential addition of acetyl-CoA to the
which transports TGs from intestine to liver. In growing fatty acid chain.
circulation, CM is acted on by another lipase • NADPH, produced by the HMP pathway and
known as lipoprotein lipase (LPL). LPL is attached enzyme malate dehydrogenase, provide the
to the basement membrane of endothelial cells reducing equivalents.
lining the capillaries, and digests TGs present in
CM and other lipoproteins. The FFAs and glycerol 3.4 Overview of Fatty Acid Synthesis
released are taken up by the extrahepatic tissues
for energy production. • When the chain is 16-C long, it is released as
palmitate.
• Further fates of palmitate include:
3.3 De Novo Fatty Acid Synthesis
◦ further elongation of the fatty chain (which
(Lipogenesis) occurs in peroxisomes)
• Site: the liver is the main site; other sites include ◦ desaturation (introduction of a double bond
the kidneys, brain, mammary glands and adipose between C1 and 10 to form unsaturated fatty
tissue (not an important site in humans). acid (FA))
• Cellular location: cytoplasm. ◦ esterification of fatty acids with glycerol to form
• Enzymes required: acetyl-CoA carboxylase, fatty TGs: major storage form of fuel (stored in
acid synthase (FAS) complex. adipose tissue)
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 Carbohydrate, Protein and Lipid Metabolism

Mitochondrion Cytoplasm Insulin

Citrate
+ +
shuttle
Acetyl-CoA CO2
Acetyle-CoA Citrate Citrate + carboxylase Fatty acid
(biotin) synthase Fatty acid
Acetyl-CoA Malonyl- palmitate
CoA NADPH (16:0)
OAA OAA
CO2

Malate
Pyruvate
PDH NADP+
carboxylase
(biotin) Malic
enzyme
NADPH

Pentose Phosphate Pathway

Pyruvate Pyruvate Glucose
and Glycolysis

Figure 36.4 Pyruvate cycle.

◦ esterification with cholesterol to form • Long-term regulation: occurs by induction/

cholesteryl esters repression of the carboxylase gene by insulin/
• For these fates, the palmitate must be activated to glucagon during the fed/starvation state
palmitoyl CoA (by the enzyme acyl-CoA respectively.
synthetase; requires ATP as energy source). • FAS enzyme undergoes induction and repression
by insulin and glucagon, respectively.
3.5 Regulation of Lipogenesis
3.6 Fatty Acid Oxidation (Breakdown)
• Rate-limiting reaction: acetyl-CoA carboxylase step.
• Fatty acid oxidation is the major source of energy
• Short-term regulation:
for ATP synthesis in humans.
◦ Allosteric modification: citrate is the most • Muscles use fatty acids for their energy needs
important positive modulator and increases during rest. The brain and RBCs do not use
enzyme activity manifold by causing fatty acids as a source of energy. The β-
polymerisation of the enzyme. oxidation pathway is not well developed in the
◦ FFA is the most important negative modulator brain and nervous tissues, and RBCs do not
and inhibits the enzyme by disrupting the have mitochondria. Such tissues use glucose as
polymerised form. their primary energy source; other tissues being
◦ Covalent modification: the enzyme is active the lens of the eye, the retina and the placenta.
in dephosphorylated form, brought about by • Fatty acid is oxidised in the mitochondria by
insulin (which has high concentrations in a process known as β-oxidation.
the fed state) by activating a specific • Fatty acid is first activated to fatty acyl-CoA, then
phosphatase enzyme, which removes the enters mitochondrial matrix by a carnitine
phosphate group from the enzyme. In transport system present in mitochondrial
a starved state, glucagon is high and causes membranes. The enzymes involved are carnitine-
phosphorylation of the enzyme by activating acyl (palmitoyl) transferase I (CPT I):
a kinase enzyme and making carboxylase
inactive. ◦ carnitine-acylcarnitine translocase (CAT)

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 Smita Kaushik

◦ carnitine-acyl (palmitoyl) transferase II (CPT II) This is the deciding factor in mitochondria for acetyl-
• Deficiency of any or all of these enzymes can lead CoA to enter the TCA or ketogenesis pathway:
to decrease in β-oxidation, causing muscular adequate oxaloacetate (fed state) → acetyl-CoA
weakness and hypoglycaemia. enters the TCA; low OAA → it enters ketogenesis.
• Once inside the mitochondria, fatty-acyl-CoA
undergoes a series of four reactions repeatedly 3.8 Utilisation of Ketone Bodies
to cause breakdown of acyl chain in 2-C units by Tissues During Starvation
sequentially from the carboxyl end of the fatty
chain. This 2-C unit is acetyl-CoA. This • All tissues except the liver can utilise ketone bodies
process is known as β-oxidation, as the bond as a source of energy as they contain an enzyme
between α and β carbon atoms of acyl chain is called thiophorase (i.e., succinyl CoA-
broken. The four enzymes catalysing these acetoacetate CoA transferase).
steps are: • Increased production of ketone bodies, causing an
+ increase in blood ketone body levels, is
1. acyl-CoA dehydrogenase, linked to FAD
ketonaemia. Normal blood values are 1 mmol/L.
2. enoyl-CoA hydratase
Excess is excreted in urine, ketonuria, which is
3. β-hydroxy acyl-CoA dehydrogenase, linked to seen in prolonged starvation, uncontrolled DM,
NAD+ heavy lactation and severe exercise.
4. β-ketothiolase
• NADH + H+ and FADH2 produced in each cycle 3.9 Metabolism of Unsaturated
undergo oxidative phosphorylation for ATP
generation: 2.5 ATP for each NADH and 1.5 ATP Fatty Acids
for each FADH2. • Monounsaturated fatty acids can be synthesised in
• Acetyl-CoA cleaved off after every cycle goes to the the body as humans can introduce double bonds
TCA cycle for ATP generation: 10 ATP are anywhere between C-1 (the carboxyl-C) and C-10,
generated from each molecule of acetyl-CoA. but not beyond it. The most common double bond
is between C9 and C10. This process is facilitated
3.7 Ketogenesis (Synthesis of by enzyme: desaturase; present in endoplasmic
reticulum. The process also requires cytochrome
Ketone Bodies) b5, NAD(P)H and oxygen O2.
• Organ: liver. • PUFAs are essential in the diet as they cannot be
• Site: mitochondria of hepatocytes. synthesised in the body.
• Substrate: acetyl-CoA. • Trans fatty acids are found in ruminant fat and are
• Product: acetone, acetoacetate, β- present in hydrogenated vegetable fat. In the body
hydroxybutyrate are the ketone bodies. they behave as, and are metabolised as, saturated
• Enzymes required: 3-hydroxy-3-methyl-glutaryl fatty acids. They also tend to raise blood levels of
(HMG) CoA synthase, HMG CoA lyase, LDL and lower HDL levels, thus are atherogenic in
3-hydroxybutyrate dehydrogenase. nature. Trans fats tend to antagonise the
• Ketone bodies serve as fuel for tissues such as metabolism of essential fatty acids (EFAs) and also
muscles, especially cardiac muscle, slow-twitch exacerbate their deficiency.
muscle and renal cortex under normal conditions.
During prolonged starvation, most of the tissues
switch from glucose to ketone bodies as the 3.10 Metabolism of Eicosanoids
primary source of energy, except RBCs, the lens, • Arachidonic acid (from the plasma membrane) is
the retina and the fast-twitch muscle. The brain the precursor for eicosanoids. They are
uses ketone bodies during prolonged starvation. prostaglandins (PGs), thromboxane (TX)
• Regulation of ketogenesis is maintained by (1) (prostanoids), leukotriene (LT) and lipoxin (LX).
concentration of FFAs in the blood, (2) uptake by They act as local hormones, having paracrine and
liver, (3) concentration of OAA in the TCA cycle. autocrine effects.

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 Carbohydrate, Protein and Lipid Metabolism

• Prostanoids are synthesised by the cyclooxygenase complex lipids in neurons, causing

(COX) pathway. The COX enzyme is inhibited by neurodegeneration and shortening of
nonsteroidal anti-inflammatory drugs (NSAIDs), lifespan. The rate of synthesis of these lipids is
so inflammatory action of PGs can be inhibited by normal. Treatment consists of enzyme
giving NSAIDs, which inhibits the enzyme replacement therapy, bone marrow transplant
cyclooxygenase irreversibly (suicidal inhibition). or gene therapy. Some of the important
• There are two isoenzymes of COX: COX-1 and diseases are:
COX-2. NSAIDS (e.g., aspirin) inhibit both 1. Tay–Sachs disease: caused by deficiency of
isoenzymes. COX-1 has a gastro-protective action enzyme hexosaminidase A, leading to
(decreases gastric acid secretion, but no effect on accumulation of gangliosides.
gastric mucus secretion), but since COX-1 is also 2. Fabry disease: caused by deficiency of enzyme
inhibited, NSAID intake is associated with gastric α-galactosidase, leading to the accumulation of
irritation. Coxibs are drugs that selectively inhibit a special ceramide. It is X-linked recessive in
COX-2 and have gastro-protective action. inheritance.
• Low-dose aspirin inhibits COX and prevents 3. Gaucher’s disease: due to deficiency of the
vasoconstriction and platelet aggregation (by enzyme β-galactosidase, there is accumulation
inhibiting thromboxane, TX2, synthesis) and of glucosylceramide.
promotes vasodilatation (uninterrupted role of
4. Niemann–Pick disease: due to deficiency of the
PGI2: prostacyclin).
enzyme sphingomyelinase, there is
• Omega-3 fatty acid, found in cod-liver oil, is very accumulation of sphingomyelin.
cardioprotective as it causes production of TX3
and prostaglandin I3 (PGI3), whose overall effect is • These diseases cause intellectual disability,
cardioprotective: leading to vasodilatation and hepatomegaly, skeletal deformities, and so on.
decreased platelet aggregation. Additionally, levels Many are fatal in early life.
of LDL, VLDL, triglycerides and cholesterol are
also low in individuals who regularly consume 3.12 Cholesterol Metabolism
omega-3 fatty acids in their diet.
• Cholesterol is present in all cells and plasma either
• Prostaglandins (PGE and PGF) have roles as as free cholesterol or combined with a long-chain
abortifacient, and for induction of labour in the fatty acid as cholesteryl ester (the storage form). In
term uterus. plasma, both forms are transported as
• Leukotrienes and lipoxins are mediators of lipoproteins. It is an amphipathic molecule and an
inflammatory reactions, synthesised by essential structural component of membranes. It
lipoxygenase enzyme system. gives rise to many important biomolecules in the
body.
3.11 Phospholipids • The body gets cholesterol from the diet as well as it
• Lysolecithin is utilised for production of the lung is synthesised in all nucleated cells in the body. The
surfactant, dipalmitoyl-phosphatidylcholine in liver and intestine are the major sites of synthesis.
lung alveoli. In babies born prematurely, 3.12.1 Cholesterol Synthesis
concentration of lung surfactant is very low (L:S
<2) and such babies are prone to develop infant • Acetyl-CoA is the precursor molecule for
respiratory distress syndrome (IRDS). cholesterol synthesis. See Figure 36.5.
• Multiple sclerosis is a demyelinating disease, with
loss of phospholipids and sphingolipids from 3.12.2 Regulation of Cholesterol Biosynthesis
white matter; thus, its lipid composition starts to • HMG-CoA reductase is the rate-limiting and
resemble that of grey matter. committed step in the cholesterol biosynthesis
• Lipid storage diseases (sphingolipidoses) are pathway.
a group of inherited diseases caused by • Statins are a group of drugs that inhibit cholesterol
a genetic defect in the catabolism of synthesis by competitively inhibiting HMG-CoA
sphingolipids. There is accumulation of reductase.

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 Smita Kaushik

synthesis of other steroid compounds such as

Acetyl CoA Acetoacetyl CoA
steroid hormones, bile salts and vitamin D.

HMG-CoA 3.12.4 Transport of Cholesterol Between Tissues

Synthase
• In blood, cholesterol is transported in
lipoproteins, mainly as cholesteryl esters. LDL is
the lipoprotein with maximum concentration of
cholesterol.
3-hydroxy-3-methyl-
• Dietary cholesterol equilibrates with plasma
glutaryl-CoA
(HMG-CoA) cholesterol in days, and with tissue cholesterol in
Glucagon, AMP weeks.
2 NADPH • Dietary cholesterol, as cholesteryl esters, is first
HMG-CoA Rate limiting step hydrolysed to free cholesterol by the enzyme
SREBP Synthesis
reductase cholesteryl esterase, which is then absorbed by
intestinal epithelium along with other lipids and
CoA + 2 NADP+
Insulin fat-soluble vitamins. Dietary lipids and cholesterol
are then incorporated, along with cholesterol
Mevalonic Acid
synthesised in the intestinal epithelial cells, into
Statins 3 ATP Mevalonate Pathway chylomicrons. CM delivers most of the cholesterol
to the liver in chylomicron remnants. Liver
6 Isopentenyl pyrophosphate
secretes most cholesterol in the form of VLDL,
cholesterol is retained as VLDL transforms into
Squalene
intermediate density lipoprotein (IDL) and then
into LDL. LDL is finally taken up by LDL receptors
in liver and extrahepatic tissues.
Lanosterol • Excretion of cholesterol: cholesterol is excreted
from the body as cholesterol in bile or as bile acids.
The steroid nucleus cannot be degraded.
Cholesterol
Figure 36.5 Biosynthesis of cholesterol. 3.12.5 Synthesis of Bile Acids
SREBP – Sterol-regulatory-element-binding-protein
• The primary bile acids are synthesised in the liver
from cholesterol. They are cholic acid (major
3.12.3 Cholesterol Balance at the Cellular Level form) and chenodeoxycholic acid. They are
Intracellular cholesterol concentration is regulated by conjugated with taurine and glycine to form
various factors: taurocholic acid and glycocholic acid, and are
stored in bile in the gall bladder.
1. An increase in cholesterol level is caused by: (a) an
• The rate-limiting enzyme is 7α-hydroxylase. It is
increase in cellular uptake of cholesterol-
containing lipoproteins by specific lipoprotein a microsomal enzyme, requires oxygen, NADPH,
receptors on the cell membrane; for example, LDL cytochrome P450 and ascorbic acid (vitamin C).
receptor or scavenger receptor, (b) uptake of free • The bile acids or salts enter the intestine along
cholesterol from cholesterol-rich lipoproteins to with bile, where they are further metabolised by
the cell membrane, (c) cholesterol biosynthesis, the intestinal bacteria and form secondary bile
(d) hydrolysis of cholesteryl esters by cholesteryl acids or salts, deoxycholic acid and lithocholic
ester hydrolase. acid.
2. A decrease in cholesterol level: (a) due to • Of the primary and secondary bile acids in the
cholesterol efflux from the membrane to HDL via intestine, 98–99% are absorbed in the ileum and
specific membrane receptors, (b) esterification of returned to the liver via portal circulation. This is
cholesterol by acyl-CoA: cholesterol acyl called the enterohepatic circulation. The small
transferase, (c) utilisation of cholesterol for the fraction that escapes absorption is excreted in the

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 Carbohydrate, Protein and Lipid Metabolism

faeces. This is the only pathway for elimination of • Ezetimibe reduces blood cholesterol by inhibiting
cholesterol from body. its intestinal absorption.
• Dietary fibre has a major role to play in decreasing
3.12.6 Clinical Aspects Related to Cholesterol intestinal absorption of cholesterol, other fats,
• Normal serum cholesterol is less than 180 mg/dL. glucose, toxins, and so on by binding to it. Inclusion
Values more than 200 mg/dL is a major risk factor of dietary fibre in the diet is highly recommended as
in promoting atherosclerosis, which is it has multiple beneficial effects: it is helpful in
characterised by deposition of cholesterol and maintaining normal blood cholesterol, triglyceride
cholesteryl esters present in lipoproteins into the and glucose levels, and it decreases the incidence of
artery wall. Prolonged elevated levels of blood colon carcinoma by absorbing toxins and other
VLDL, IDL, LDL (especially oxidised LDL) and oxidants implicated in carcinogenesis.
CM remnants, due to diseases like DM,
3.12.7 Hypercholesterolaemias
hypothyroidism, lipid nephrosis and
hyperlipidaemia lead to atherosclerosis.
Conversely, there is an inverse relationship Familial hypercholesterolemia
between blood HDL (HDL2) and the incidence of • autosomal dominant inheritance
coronary heart disease. Thus, LDL:HDL • defect in LDL receptor gene, leading to
cholesterol ratio is a good predictor to assess the inhibition of cellular cholesterol uptake and
risk of coronary artery disease (CAD). increased LDL-cholesterol
• Diet and lifestyle changes have an important role • very high risk of developing CAD and myocardial
to play in maintaining normal blood cholesterol. infarction (MI)
• Although genetic factors are most important in • xanthomas (cholesterol deposits in skin),
determining an individual’s blood cholesterol xanthelasma (deposits around eye), chest pain
levels, dietary and environmental factors also play • genetic mutation on chromosome 19
a part. Inclusion of polyunsaturated fatty acids • blood total cholesterol levels are more than
(PUFAs) (corn oil and sunflower seed oil) and 250 mg/dL in children or >300 mg/dL in adults
monounsaturated fatty acids (MUFAs) instead of • treatment includes drugs like statins, which
saturated fatty acids (e.g., butter, palm oil, animal inhibit cholesterol synthesis. Clofibrate decreases
fat) is an important step towards a healthy cholesterol absorption from intestine and, in
lifestyle. Additionally, avoiding refined severe cases, LDL-apheresis is used
carbohydrates (sucrose, fructose, refined wheat
flour, etc.) help in lowering triacylglycerols in 3.12.8 Disorders of Plasma Lipoproteins
blood.
Defects in lipoprotein synthesis, transport or breakdown
• The cholesterol-lowering effect of PUFAs and
can lead to inherited primary dyslipoproteinaemias.
MUFAs has been attributed to their role in
There can be either hypo- or hyperlipoproteinaemia.
upregulating LDL receptors on cell membranes,
thereby increasing catabolism of LDL, which is the
Secondary dyslipoproteinemias
main atherogenic lipoprotein.
Dyslipoprotenemias are associated with DM, hypothyr-
• Lifestyle factors such as excessive emotional stress,
oidism, nephrotic syndrome and atherosclerosis. See
smoking, high blood pressure, male sex,
Figure 36.4.
postmenopausal women, abdominal obesity and
heart disease increase the risk of atherosclerosis.
• When diet and lifestyle changes fail, then Lipoprotein chemistry
hypolipidaemic drugs help in reducing serum • Dietary fats absorbed from the intestine, and
cholesterol and TG levels. Statins (atorvastatin, lipids synthesised in the liver and adipose
simvastatin, fluvastatin, etc.) are a group of drugs tissue have to be transported among the tissues
that act on HMG-CoA reductase enzyme and and organs for utilisation and storage. Lipids
competitively inhibit the enzyme and also are insoluble in water, so they need
upregulate LDL receptor activity, thus reducing a hydrophilic medium for transportation. This
blood cholesterol. is accomplished by associating the nonpolar
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 Smita Kaushik

Table 36.4 Secondary hypercholesterolaemia Liver and lipid metabolism

Endocrine: The liver facilitates digestion and absorption of lipids
• Hypothyroidism by production of bile, which contains cholesterol and
• Hypopituitarism bile salts. Bile salts are synthesised in the liver. The liver
• DM actively synthesises and oxidises fatty acids. It also
Metabolic: synthesises TGs and phospholipids (PLs). During pro-
• Gaucher’s disease longed starvation, the liver synthesises ketone bodies
• Glycogen storage disease from fatty acids (ketogenesis); hence, it plays a pivotal
• Tay–Sachs disease
role in the synthesis and metabolism of lipoproteins.
• Niemann–Pick disease
Renal:
• Nephrotic syndrome Fatty liver
• Haemolytic uraemic syndrome • Extensive accumulation of lipids, especially TGs in
Liver: the liver leads to fatty liver. Nonalcoholic fatty
• Hepatitis liver disease is the most common liver disorder in
• Cholestasis (intrahepatic cholestasis, congenital the world. Chronic fatty liver can lead to the
biliary atresia)
development of inflammatory and fibrotic
Medication: changes causing nonalcoholic steatohepatitis,
• Androgens which can progress to liver cirrhosis,
• Diuretics
hepatocarcinoma and liver failure.
• Glucocorticoids
• Immunosuppressive agents (cyclosporine, tacrolimus) • Categories of fatty liver:
• Oral contraceptives 1. Chronic elevation of plasma FFAs:
• Retinoids
Miscellaneous:
◦ high-fat diet
• Anorexia nervosa ◦ uncontrolled DM
• Systemic lupus erythematosus ◦ starvation
• Idiopathic hypercalcaemia
• Klinefelter
2. Metabolic block in production of plasma
lipoproteins:
◦ block in apolipoprotein synthesis
TGs and cholesteryl esters with amphipathic ◦ block in lipoprotein synthesis from
lipids like phospholipids, cholesterol and apoprotein and lipids
proteins to make water-miscible lipoproteins.
◦ lack of PLs found in lipoproteins
Thus, lipids are transported in plasma as
◦ failure in secretion of lipoproteins
lipoproteins.
• There are four major classes of lipids; namely, TGs
(16%), phospholipids (30%), cholesterol (14%), Causes of fatty liver
cholesteryl esters (36%) and a very small fraction of • Chemicals such as puromycin (an antibiotic),
unesterified long-chain fatty acids: FFAs (4%). FFAs carbon tetrachloride (CCl4), ethionine and
are metabolically the most active fraction of plasma chloroform.
lipids. • Metals such as lead, phosphorus, arsenic and
• There are four major groups of lipoproteins, orotic acid.
depending on the content of fat and protein. Fat is • Deficiency of antioxidant vitamins such as
lighter than water, hence the density of E, B complex, selenium and essential fatty
a lipoprotein decreases as proportion of fat or lipid acids
to protein ratio increases. Based on the density, • Ethanol is an important cause of fatty liver.
they are classified into four classes: • Alcoholic fatty liver is the first stage in alcoholic
1. Chylomicron liver disease. This may lead to cirrhosis.
2. VLDL • Fat accumulation is due to impaired fatty acid
3. LDL oxidation and increased lipogenesis (due to
4. HDL increased energy production during alcohol

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 Carbohydrate, Protein and Lipid Metabolism

metabolism). The enzymes involved are • Maternal glucose, FFAs, ketone bodies and
alcohol dehydrogenase and aldehyde glycerol (in small quantities) easily cross the
dehydrogenase. placenta and are used by the fetus as fuels for
• Substances that can prevent the onset of fatty liver oxidative metabolism and as lipogenic
are known as lipotropic factors. substrates.
• Many hormones promote lipolysis in adipose • Maternal cholesterol is a major source of
tissue by activating hormone-sensitive lipase cholesterol for the fetus during early gestation, but
(HSL) and increasing release of FFAs into the as the fetus grows, fetal tissues develop a high
circulation. These are epinephrine, capacity to synthesise cholesterol during late
norepinephrine, ACTH, melanocyte-stimulating pregnancy.
hormone, thyroid stimulating hormone, growth • There is maternal hypertriglyceridaemia,
hormone and vasopressin. Glucocorticoids and accumulating in VLDL, LDL and HDL. TGs do
thyroid hormones act as facilitatory factors. not cross the placental barrier, and there is
• Adipose tissue secretes hormones such as presence of lipoprotein receptors, LPL, PLA2 and
adiponectin, and leptin. Adiponectin modulates intracellular lipase activity in the placenta. These
glucose and lipid metabolism in muscle and the allow release of long-chain PUFAs (particularly
liver, and leptin tends to suppress appetite in the face docosahexaenoic acid – DHA, 22:6 omega-3) and
of sufficient food intake. Lack of leptin secretion essential fatty acids from maternal lipoproteins to
may lead to uncontrolled food intake, causing the fetus for its development.
obesity. • During the first two trimesters, lipid metabolism is
• Brown adipose tissue is involved in metabolism mostly anabolic (an increase in lipogenesis and fat
when heat generation is essential. This tissue is storage) promoted by maternal hyperphagia and
active in hibernating animals (during arousal from an increased insulin sensitivity. In addition, there
hibernation), in animals exposed to cold is an increase in levels of progesterone, cortisol,
(nonshivering thermogenesis), and in newborn leptin and prolactin, which contributes to
human babies. It is responsible for diet-induced increased fat storage.
thermogenesis, where ATPs are not synthesised, • In the third trimester, lipid metabolism is in
but energy is dissipated as heat (to maintain body a net catabolic phase, mainly due to insulin
temperature in newborns). resistance, causing an increase in lipid
breakdown. Additionally, increase in human
Pregnancy and lipid metabolism placental lactogen stimulates lipolysis in
• There is an increased body fat accumulation adipose tissue.
during early pregnancy. It is associated with both • Dyslipidaemia during pregnancy may lead to
increased dietary intake and lipogenesis. preeclampsia or gestational DM in the mother,
• During late pregnancy, there is an increased and poses a high risk of developing atherosclerosis
lipolysis in fat depots; the FFAs and glycerol being later in life for the fetus.
used for fetal development.

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