A general overview of the major metabolic pathways

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

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

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

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.

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.

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

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.

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.

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

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.

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.

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.

A general overview of the major metabolic pathways

Enzymatic control of metabolic pathways

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.

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

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

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.

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.

Hormone control

Further reading

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