A general overview of the major metabolic pathways

Prof. Doutor Pedro Silva

Assistant Professor, Universidade Fernando Pessoa

Metabolism is the set of chemical rections that occur in a cell, which enable it to keep living, growing and dividing. Metabolic processes are usually classified as:

  • catabolism - obtaining energy and reducing power from nutrients.
  • anabolism - production of new cell components, usually through processes that require energy and reducing power obtained from nutrient catabolism.

    There is a very large number of metabolic pathways. In humans, the most important metabolic pathways are:

  • glycolysis - glucose oxidation in order to obtain ATP
  • citric acid cycle (Krebs' cycle) - acetyl-CoA oxidation in order to obtain GTP and valuable intermediates.
  • oxidative phosphorylation - disposal of the electrons released by glycolysis and citric acid cycle. Much of the energy released in this process can be stored as ATP.
  • pentose phosphate pathway - synthesis of pentoses and release of the reducing power needed for anabolic reactions.
  • urea cycle - disposal of NH4+ in less toxic forms
  • fatty acid β-oxidation - fatty acids breakdown into acetyl-CoA, to be used by the Krebs' cycle.
  • gluconeogenesis - glucose synthesis from smaller percursors, to be used by the brain.

    Click on the picture to get information on each pathway

    Gluconeogenesis Regenerating oxaloacetate Glycogen synthase Glucose-6-phosphatase (Gluconeogenesis) Fructose-1,6-bisphosphatase (Gluconeogenesis) Incorporation of the first nitrogen atom Transamination Pentose phosphate pathway Fatty acids beta-oxidation Fatty acids synthesis Glycogen degradation Glycolysis Glycolysis Pyruvate kinase (Glycolysis) Phosphoglucomutase Glucose activation Carbamoyl-phosphate synthesis Argininosuccinate breakdown Pyruvate decarboxylation Citrate synthase Isocitrate decarboxylation GTP synthesis Aldolase (Glycolysis) Incorporation of the second nitrogen atom Arginine hydrolysis and urea synthesis Glycogen metabolism Aminoacid degradation and urea cycle Citric acid cycle NADH formation (Glycolysis) Ketogenesis

    Metabolic pathways interact in a complex way in order to allow an adequate regulation. This interaction includes the enzymatic control of each pathway, each organ's metabolic profile and hormone control.

  • Enzymatic control of metabolic pathways

    Regulation of glycolysis

    Metabolic flow through glycolysis can be regulated at three key points:

    Regulation of gluconeogenesis

    Flow is regulated in the gluconeogenesis-specific reactions. Pyruvate carboxilase is activated by acetyl-CoA, which signals the abundance of citric acid cycle intermediates, i.e., a decreased need of glucose.

    Regulation of the citric acid cycle

    The citric acid cycle is regulated mostly by substrate availability, product inhibition and by some cycle intermediates.

    Regulation of the urea cycle

    Carbamoyl-phosphate sinthetase is stimulated by N-acetylglutamine, which signals the presence of high amounts of nitrogen in the body.

    Regulation of glycogen metabolism

    Liver contains a hexokinase (hexokinase D or glucokinase)with low affinity for glucose which (unlike "regular" hexokinase) is not subject to product inhibition. Therefore, glucose is only phosphrylated in the liver when it is present in very high concentrations (i.e. after a meal). In this way, the liver will not compete with other tissues for glucose when this sugar is scarce, but will accumulate high levels of glucose for glycogen synthesis right after a meal.

    Regulation of fatty acids metabolism

    Acyl-CoA movement into the mitochondrion is a crucial factor in regulation. Malonyl-CoA (which is present in the cytoplasm in high amounts when metabolic fuels are abundant) inhibits carnitine acyltransferase, thereby preventing acyl-CoA from entering the mitochondrion. Furthermore, 3-hydroxyacyl-CoA dehydrogenase is inhibited by NADH and thiolase is inhibited by acetyl-CoA, so that fatty acids wil not be oxidized when there are plenty of energy-yielding substrates in the cell.

    Regulation of the pentose phosphate pathway

    Metabolic flow through the pentose phosphate pathway is controled by the activity of glucose-6-phosphate dehydrogenase, which is controlled by NADP+ availability.

    Metabolic profiles of key tissues

    Brain

    Usually neurons use only glucose as energy source. Since the brain stores only a very small amount of glycogen, it needs a steady supply of glucose. During long fasts, it becomes able to oxidize ketone bodies.

    Liver

    The maintenance of a fairly steady concentration of glucose in the blood is one of the liver's main functions. This is accomplished through gluconeogenesis and glycogen synthesis and degradation. It synthesizes ketone bodies when acetyl-CoA is plenty. It is also the site of urea synthesis.

    Adipose tissue

    It synthesizes fatty acids and stores them as triacylglycerols. Glucagon activates a hormone-sensitive lipase, which hydrolizes triacylglycerols yielding glycerol and fatty acids. These are then released into the bloodstream in lipoproteins.

    Muscle

    Muscles use glucose, fatty acids, ketone bodies and aminoacids as energy source. It also contains a reserve of creatine-phosphate, a compound with a high phosphate-transfer potential that is able to phosphorilate ADP to ATP, thereby producing energy without using glucose. The amount of creatine in the muscle is enough to sustain about 3-4 s of exertion. After this period, the muscle uses glycolysis, first anaerobically (since it is much faster than the citric acid cycle), and later (when the increased acidity slows phosphofrutokinase enough for the citric acid cycle to become non-rate-limiting) in aerobic conditions.

    Kidney

    It can perform gluconeogenesis and release glucose into the bloodstream. It is also responsible for the excretion of urea, electrolytes, etc. Metabolic acidosis may be increased by the action of the urea cycle, since urea synthesis (which takes place in the liver) uses HCO3-, thereby further lowering blood pH. Under these circunstances, nitrogen may be eliminated by the joint action of kidney and liver: excess nitrogen is first incorporated in glutamine by glutamine synthetase. Kidney glutaminase then cleaves glutamine in glutamate e NH3, which the kidney immediately excretes. This process allows nitrogen excretion without affecting blood bicarbonate levels.

    Hormone control

    Hormone control is mainly effected through the action of two hormones synthesized by the pancreas: insulin and glucagon. Insulin is released by the pancreas when blood glucose levels are high, i.e., after a meal. Insulin stimulates glucose uptake by the muscle, glycogen synthesis, and triacylglyceride synthesis by the adipose tissue. It inhibits gluconeogenesis and glycogen degradation. Glucagon is released by pancreas when blood glucose levels drop too much. Its effects are opposite those of insulin: in liver, glucagon stimulates glycogen degradation and the absorption of gluconeogenic aminoacids. It inhibits glycogen synthesis and promotes the release of fatty acids by adipose tissue.

    Further reading

    cover Biochemistry, by Donald Voet & Judith Voet

    An excellent text. It presents Biochemistry with frequent references to organic chemistry and biochemical logic. Highly reccommended for students of Biochemistry, Chemistry and Pharmaceutical Sciences.

    cover Biochemistry, Stryer

    A widely used classical text, frequently updated and re-issued.

    cover Textbook of Biochemistry with Clinical Correlations, Thomas Devlin

    Strongly advised to students in Nursing, Medicine, Dentistry, etc. Plenty of examples of application of biochemical knowledge to clinical cases.

    cover Principles of Biochemistry, Lehninger

    A widely used classical text, frequently updated and re-issued.

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