A general overview of the major metabolic pathways (2024)

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:

gluconeogenesis - glucose synthesis from smaller percursors, to be used by the brain.

Click on the picture to get information on each pathway

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:

hexokinase: is inhibited by glucose-6-P (product inhibition)
phosphofructokinase: is inhibited by ATP and citrate (which signals the abundance of citric acid cycle intermediates). It is also inhibited by H⁺, which becomes important under anaerobiosis (lactic fermentation produces lactic acid, resulting on a lowering of the pH ). Probably this mechanism prevents the cell from using all its ATP stock in the phosphofrutokinase reaction, which would prevent glucose activation by hexokinase. It is stimulated by its substrate (fructose-6-phosphate), AMP and ADP (which signal the lack of available energy), etc.
pyruvate kinase: inhibited by ATP, alanine, free fatty acids and acetyl-CoA. Activated by fructose-1,6-bisphosphate and AMP

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.

pyruvate dehydrogenase: is inhibited by its products, acetyl-CoA and NADH
citrate synthase: is inhibited by its product, citrate. It is also inhibited by NADH and succinyl-CoA (which signal the abundance of citric acid cycle intermediates).
isocitrate dehydrogenase and a-ketoglutarate dehydrogenase: like citrate synthase, these are inhibited by NADH and succinyl-CoA. Isocitrate dehydrogenase is also inhibited by ATP and stimulated by ADP. All aforementioned dehydrogenases are stimulated by Ca²⁺. This makes sense in the muscle, since Ca²⁺ release from the sarcoplasmic reticulum triggers muscle contraction, which requires a lot of energy. This way, the same "second messenger" activates an energy-demanding task and the means to produce that energy.

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 gluco*kinase)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.

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.

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.

	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.		Biochemistry, Stryer A widely used classical text, frequently updated and re-issued.
	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.		Principles of Biochemistry, Lehninger A widely used classical text, frequently updated and re-issued.