METABOLISM

CONCEPT l Metabolism is a highly coordinated cellular activity in which many multi-enzyme systems (metabolic pathways) cooperate to (i) Obtain chemical energy by
capturing solar energy or degrading energy-rich nutrients from the environment; (ii) Convert nutrient molecules into the cell's own characteristic molecules,

MAP
including precursors of macromolecules; (iii) Polymerise monomeric precursors into macromolecules: (proteins, nucleic acids and polysaccharides) and (iv)
Synthesise and degrade biomolecules required for specialised cellular functions, such as membrane lipids, intracellular messengers and pigments.
l Metabolic pathways fall into three categories: (i) Anabolic pathways which are those involved in the synthesis of larger and more complex compounds from
smaller precursors; (ii) Catabolic pathways which are involved in the breakdown of larger molecules, commonly involving oxidative reactions and are
exothermic and (iii) Amphibolic pathways which occur at the "crossroads" of metabolism, acting as links between the anabolic and catabolic pathways, e.g.,
the citric acid cycle.

Carbohydrate Protein Fat

Digestion and absorption
Metabolism of
Glucose Amino acids
Fatty acids Carbohydrates, Proteins and Lipids
+ Glycerol
The products of digestion of dietary carbohydrates, lipids and proteins are glucose, fatty acid +
l
glycerol and amino acids, respectively.
Transamination l All the products of digestion are metabolised to a common product, acetyl-CoA, which is then oxidised by
Glycolysis the citric acid cycle.
b-Oxidation
l Glucose is metabolised to pyruvate by the pathway of glycolysis. Aerobic tissues metabolise pyruvate to acetyl-CoA,
which can enter the citric acid cycle for complete oxidation to CO2 and H2O, linked to the formation of ATP in the
Acetyl-CoA
process of oxidative phosphorylation. Glycolysis can also occur anaerobically when the end product is lactate.
l Fatty acids may be oxidised to acetyl-CoA by b-oxidation or esterified with glycerol, forming triacylglycerol (fat) as

Citric the body's main fuel reserve. Acetyl-CoA formed by b-oxidation may undergo three fates : (i) It is oxidised to
acid CO2 + H2O via the citric acid cycle ; (ii) It is the precursor for synthesis of cholesterol and other steroids; (iii) In the
cycle 2H ® ATP liver, it is used to form ketone bodies (acetoacetate and 3- hydroxybutyrate) that are important fuels in
prolonged fasting.
l The non-essential amino acids, which are supplied in the diet can also be formed from metabolic
2CO2
Fig.: Outline of pathways for the catabolism of dietary
intermediates by transamination using the amino nitrogen from other amino acids. After
carbohydrate, protein and fat deamination, amino nitrogen is excreted as urea and the carbon skeletons that remain
after transamination may : (i) be oxidised to CO2 via the citric acid cycle; (ii) be used
to synthesise glucose (gluconeogenesis) or; (iii) form ketone bodies
which may be oxidised or be used for synthesis of
fatty acids.
Integration of metabolic
pathways at tissue and organ level
l At tissue and organ level, the nature of substrates entering and Plasma proteins
metabolites leaving tissues and organs is defined.
l Amino acids and glucose resulting from digestion of proteins and carbohydrates,
Liver
respectively are absorbed via hepatic portal vein. Urea Protein
l Excess glucose is converted to glycogen (glycogenesis) or to fatty acids (lipogenesis) in
Amino acids
liver.
l In between the meals, glycogen is broken down to glucose (glycogenolysis) and non- Glucose CO2
carbohydrate metabolites (lactate, glycerol, etc.) are converted to glucose (gluconeogenesis) Amino acids
in liver. Glycogen
Protein
l Liver synthesises major plasma proteins and deaminates amino acids that are in excess, forming urea
which is transported to kidney and excreted. Urea Lactate Amino acids
l Skeletal muscles utilise glucose both aerobically forming CO2 and anaerobically forming lactate.
Alanine
l Lipids in the diet are hydrolysed to monoacylglycerols and fatty acids in the gut, packaged with
Erythrocytes Glucose
protein and secreted into the lymphatic system and then into the bloodstream as chylomicrons. It is phosphate
CO2
first metabolised by tissues that have lipoprotein lipase, which hydrolyses the triacylglycerol, Glucose
Kidney
Urine Glycogen
releasing fatty acids.
Diet
l The other major source of long-chain fatty acids is synthesi from carbohydrate (lipogenesis) in Glucose Carbohydrate
Protein Muscle
adipose tissue and the liver. Blood plasma Amino acids

l Adipose tissue triacylglycerol is hydrolysed (lipolysis) and the fatty acids are transported, Small intestine
bound to serum albumin; they are taken up by most tissues (but not brain or Fig.: Transport and fate of carbohydrate and amino acid substrates and metabolites
erythrocytes) and either esterified to triacylglycerols for storage or oxidised as a fuel.
Free fatty acids
l In the liver, triacylglycerol arising from lipogenesis, free fatty acids and
chylomicron remnants are secreted into the circulation in very low
Glucose CO2
density lipoprotein (VLDL) form. This triacylglycerol undergoes a Fatty Ketone
fate similar to that of chylomicrons. acids bodies
Est

l Partial oxidation of fatty acids in the liver leads to

erification
lysis

ketone body production (ketogenesis).

Lipo

Blood Triacyl-
glycerol
plasma
Liver
Ve lipop LDL)

CO2
ry

Glycogen Cytosol Lipoprotein

low rote

Fatty
lipase
(V

de in

AA Ribosome Protein acids

nsi

Est
ty

erification
olysis

Endoplasmic Lipoprotein
Glucose Reticulum Fatty
TG
Lip

Glucose acids Lipoprotein lipase Triacyl-

Ch

Pentose
Es t

glycerol
ylo

phosphate
e rification
olysis

mi

pathway Muscle
cro

Monoacyl
Lip

ns

Triacyl- glycerol
Triose phosphate Glycerol phosphate Triacylglycerol Fatty acids glycerol
Diet +
Adipose fatty Triacyl-
Triacyl- acids
Glycerol tissue glycerol
glycerol (TG)
Glycolysis
Small intestine
Fig.: Transport and fate of lipid substrates and metabolites
Lactate
Phosphoenolpyruvate
n

Pyruvate
io
at
Gluconeogenesis

xid
O

AA
Integration of metabolic
b-

is
s
ne

CO2
e

pathways at sub-cellular level

og

AA Pyruvate
Lip

Each cell organelle, (e.g., mitochondrion) or compartment (e.g.,

l
cytosol) has specific roles that form part of the sub-cellular pattern of
Ketone
Oxaloacetate Acetyl-CoA bodies metabolic pathways.
l Compartmentation of pathways in separate sub-cellular compartments or
organelles permits integration and regulation of metabolism. There is a central role
AA Fumarate AA Citrate of the mitochondrion, since it acts as the focus of carbohydrate, lipid and amino acid
Citric acid metabolism. It contains the respiratory chain and ATP synthase as well as the
cycle CO2
AA
enzymes of the citric acid cycle, b-oxidation of fatty acids and ketogenesis.
Succinyl-CoA a-Ketoglutarate AA l Glycolysis, the pentose phosphate pathway and fatty acid synthesis all occur in the
cytosol. In gluconeogenesis, substrates such as lactate and pyruvate, which are
formed in the cytosol, enter the mitochondrion to yield oxaloacetate as a
CO2 precursor for the synthesis of glucose in the cytosol.
l The membranes of the endoplasmic reticulum contain the
AA metabolism of one or more
essential amino acids. AA enzyme system for triacylglycerol synthesis and the
AA metabolism of one or more
Mitochondrion AA ribosomes are responsible for protein
non-essential amino acids. synthesis.
AA
Fig.: Overview of major metabolic pathways cell in a liver parenchymal cell