METABOLISM

Metabolism refers to the physical and chemical processes that occur inside the cells of the
body and that maintain life. Metabolism consists of anabolism (the constructive phase)
and catabolism (the destructive phase, in which complex materials are broken

own). The transformation of the macronutrients carbohydrates, fats, and proteins in food
to energy, and other physiological processes are parts of the metabolic process. ATP
(adinosene triphosphate) is the major form of energy used for cellular metabolism.

History

Santorio Santorio (1561-1636) in his steelyard balance, from Ars de statica medecina,
first published 1614

The first controlled experiments in human metabolism were published by Santorio

Santorio in 1614 in his book Ars de statica medecina that made him famous throughout
Europe. He describes his long series of experiments in which he weighed himself in a
chair suspended from a steelyard balance (see image), before and after eating, sleeping,
working, sex, fasting, depriving from drinking, and excreting. He found that by far the
greatest part of the food he took in was lost from the body through perspiratio insensibilis
(insensible perspiration).

Metabolic pathways

A metabolic pathway is a series of chemical reactions occurring within a cell, catalyzed

by enzymes, resulting in either the formation of a metabolic product to be used or stored
by the cell, or the initiation of another metabolic pathway (then called a flux generating
step). Many pathways are elaborate, and involve a step by step modification of the initial
substance to shape it into the product with the exact chemical structure desired. Metabolic
pathways often have these properties:

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 • They contain many steps like a cascade. However, the first step is usually
irreversible. The other in between steps need not be irreversible. In fact, many
times, the pathway can go in opposite direction depending on the need of the cell.
• They are regulated, usually by feedback inhibition, or by a cycle where the end
product starts the reaction again, such as the Krebs Cycle (see below).
• Anabolic and catabolic pathways in eukaryotes are separated by either
compartmentation or by the use of different enzymes and cofactors.

Important metabolic pathways are:

General pathways

• Carbohydrate metabolism
• Fatty acid metabolism
• Protein metabolism
• Nucleic Acid metabolism

Carbohydrate Metabolism

Carbohydrates made up of carbon, hydrogen, and oxygen atoms are classified as mono-,
di-, and polysaccharides, depending on the number of sugar units they contain. The
monosaccharides—glucose, galactose, and fructose—obtained from the digestion of food
are transported from the intestinal mucosa via the portal vein to the liver. They may be
utilized directly for energy by all tissues; temporarily stored as glycogen in the liver or in
muscle; or converted to fat, amino acids, and other biological compounds.

Carbohydrate metabolism plays an important role in both types of diabetes mellitus. The
entry of glucose into most tissues—including heart, muscle, and adipose tissue—is
dependent upon the presence of the hormone insulin. Insulin controls the uptake and
metabolism of glucose in these cells and plays a major role in regulating the blood
glucose concentration. The reactions of carbohydrate metabolism cannot take place
without the presence of the B vitamins, which function as coenzymes. Phosphorous,
magnesium, iron, copper, manganese, zinc and chromium are also necessary as cofactors.

Carbohydrate metabolism begins with glycolysis, which releases energy from glucose or
glycogen to form two molecules of pyruvate, which enter the Krebs cycle (or citric acid
cycle), an oxygen-requiring process, through which they are completely oxidized. Before
the Krebs cycle can begin, pyruvate loses a carbon dioxide group to form acetyl
coenzyme A (acetyl-CoA). This reaction is irreversible and has important metabolic
consequences. The conversion of pyruvate to acetyl-CoA requires the B vitamins.

The hydrogen in carbohydrate is carried to the electron transport chain, where the energy
is conserved in ATP molecules. Metabolism of one molecule of glucose yields thirty-one
molecules of ATP. The energy released from ATP through hydrolysis (a chemical reaction
with water) can then be used for biological work.

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Only a few cells, such as liver and kidney cells, can produce their own glucose from
amino acids, and only liver and muscle cells store glucose in the form of glycogen. Other
body cells must obtain glucose from the bloodstream.

Under anaerobic conditions, lactate is formed from pyruvate. This reaction is important in
the muscle when energy demands exceed oxygen supply. Glycolysis occurs in the cytosol
(fluid portion) of a cell and has a dual role. It degrades monosaccharides to generate
energy, and it provides glycerol for triglyceride synthesis. The Krebs cycle and the
electron transport chain occur in the mitochondria. Most of the energy derived from
carbohydrate, protein, and fat is produced via the Krebs cycle and the electron transport
system.

Glycogenesis is the conversion of excess glucose to glycogen. Glycogenolysis is the

conversion of glycogen to glucose (which could occur several hours after a meal or
overnight) in the liver or, in the absence of glucose-6-phosphate in the muscle, to lactate.
Gluconeogenesis is the formation of glucose from noncarbohydrate sources, such as
certain amino acids and the glycerol fraction of fats when carbohydrate intake is limited.
Liver is the main site for gluconeogenesis, except during starvation, when the kidney
becomes important in the process. Disorders of carbohydrate metabolism include diabetes
mellitus, lactose intolerance, and galactosemia.

Protein Metabolism

Proteins contain carbon, hydrogen, oxygen, nitrogen, and sometimes other atoms. They
form the cellular structural elements, are biochemical catalysts, and are important
regulators of gene expression. Nitrogen is essential to the formation of twenty different
amino acids, the building blocks of all body cells. Amino acids are characterized by the
presence of a terminal carboxyl group and an amino group in the alpha position, and they
are connected by peptide bonds.

Digestion breaks protein down to amino acids. If amino acids are in excess of the body's
biological requirements, they are metabolized to glycogen or fat and subsequently used
for energy metabolism. If amino acids are to be used for energy their carbon skeletons are
converted to acetyl CoA, which enters the Krebs cycle for oxidation, producing ATP. The
final products of protein catabolism include carbon dioxide, water, ATP, urea, and
ammonia.

Vitamin B6 is involved in the metabolism (especially catabolism) of amino acids, as a

cofactor in transamination reactions that transfer the nitrogen from one keto acid (an acid
containing a keto group [-CO-] in addition to the acid group) to another. This is the last
step in the synthesis of nonessential amino acids and the first step in amino acid
catabolism. Transamination converts amino acids to L-glutamate, which undergoes
oxidative deamination to form ammonia, used for the synthesis of urea. Urea is
transferred through the blood to the kidneys and excreted in the urine.

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The glucose-alanine cycle is the main pathway by which amino groups from muscle
amino acids are transported to the liver for conversion to glucose. The liver is the main
site of catabolism for all essential amino acids, except the branched-chain amino acids,
which are catabolized mainly by muscle and the kidneys. Plasma amino-acid levels are
affected by dietary carbohydrate through the action of insulin, which lowers plasma
amino-acid levels (particularly the branched-chain amino acids) by promoting their entry
into the muscle.

Body proteins are broken down when dietary supply of energy is inadequate during
illness or prolonged starvation. The proteins in the liver are utilized in preference to those
of other tissues such as the brain. The gluconeogenesis pathway is present only in liver
cells and in certain kidney cells.

Disorders of amino acid metabolism include phenylketonuria, albinism, alkaptonuria,

type 1 tyrosinaemia, nonketotic hyperglycinaemia, histidinaemia, homocystinuria, and
maple syrup urine disease.

Fat (Lipid) Metabolism

Fats contain mostly carbon and hydrogen, some oxygen, and sometimes other atoms. The
three main forms of fat found in food are glycerides (principally triacylglycerol
[triglyceride], the form in which fat is stored for fuel), the phospholipids, and the sterols
(principally cholesterol). Fats provide 9 kilocalories per gram (kcal/g), compared with 4
kcal/g for carbohydrate and protein. Triacylglycerol, whether in the form of chylomicrons
(microscopic lipid particles) or other lipoproteins, is not taken up directly by any tissue,
but must be hydrolyzed outside the cell to fatty acids and glycerol, which can then enter
the cell.

Fatty acids come from the diet, adipocytes (fat cells), carbohydrate, and some amino
acids. After digestion, most of the fats are carried in the blood as chylomicrons. The main
pathways of lipid metabolism are lipolysis, betaoxidation, ketosis, and lipogenesis.

Lipolysis (fat breakdown) and beta-oxidation occurs in the mitochondria. It is a cyclical

process in which two carbons are removed from the fatty acid per cycle in the form of
acetyl CoA, which proceeds through the Krebs cycle to produce ATP, CO2, and water.

Ketosis occurs when the rate of formation of ketones by the liver is greater than the
ability of tissues to oxidize them. It occurs during prolonged starvation and when large
amounts of fat are eaten in the absence of carbohydrate.

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Lipogenesis occurs in the cytosol. The main sites of triglyceride synthesis are the liver,
adipose tissue, and intestinal mucosa. The fatty acids are derived from the hydrolysis of
fats, as well as from the synthesis of acetyl CoA through the oxidation of fats, glucose,
and some amino acids. Lipogenesis from acetyl CoA also occurs in steps of two carbon
atoms. NADPH produced by the pentose-phosphate shunt is required for this process.
Phospholipids form the interior and exterior cell membranes and are essential for cell
regulatory signals.

Cholesterol Metabolism

Cholesterol is either obtained from the diet or synthesized in a variety of tissues,

including the liver, adrenal cortex, skin, intestine, testes, and aorta. High dietary
cholesterol suppresses synthesis in the liver but not in other tissues.

Carbohydrate is converted to triglyceride utilizing glycerol phosphate and acetyl CoA

obtained from glycolysis. Ketogenic amino acids, which are metabolized to acetyl CoA,
may be used for synthesis of triglycerides. The fatty acids cannot fully prevent protein
breakdown, because only the glycerol portion of the triglycerides can contribute to
gluconeogenesis. Glycerol is only 5 percent of the triglyceride carbon.

Most of the major tissues (e.g., muscle, liver, kidney) are able to convert glucose, fatty
acids, and amino acids to acetyl-CoA. However, brain and nervous tissue—in the fed
state and in the early stages of starvation—depend almost exclusively on glucose. Not all
tissues obtain the major part of their ATP requirements from the Krebs cycle. Red blood

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cells, tissues of the eye, and the kidney medulla gain most of their energy from the
anaerobic conversion of glucose to lactate.

Anabolism

Anabolic pathways that create building blocks and compounds from simple precursors:

• Glycogenesis
• Gluconeogenesis
• Porphyrin synthesis pathway
• HMG-CoA reductase pathway, leading to cholesterol and isoprenoids.
• Secondary metabolism, metabolic pathways that are not essential for growth,
development or reproduction, but that usually have ecological function.
• Photosynthesis
o Light-dependent reaction (light reaction)
o Light-independent reaction (dark reaction)
• Calvin cycle
• Carbon fixation
• Glyoxylate cycle

Catabolism

• Glucose catabolism

Drug metabolism

Drug metabolism pathways, the modification or degradation of drugs and other

xenobiotic compounds through specialized enzyme systems:

• Cytochrome P450 oxidase system

• Flavin-containing monooxygenase system
• Alcohol metabolism

Nitrogen metabolism

Nitrogen metabolism includes the pathways for turnover and excretion of nitrogen in
organisms as well as the biological processes of the biogeochemical nitrogen cycle:

• Urea cycle, important for excretion of nitrogen as urea.

• Biological nitrogen fixation
• Nitrogen assimilation
• Nitrification
• Denitrification
• Human iron metabolism

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