Regulation of indivdual metabolic pathways

Regulation of individual metabolic pathways is implemented through regulatory enzymes. Metabolic pathways take place in different compartments of the cell. They are affected both hormonally and nervously at the level of the entire organism. Many are dependent on the energy state of the cell, the speed of others depends only on the availability of the substrate.

ATP synthesis
The electron transporting chain is primarily controlled at the level of the need for ATP, or of ADP supply. Inhibition occurs in the absence of oxygen (hypoxia) or in the presence of inhibitors (e.g. cyanide ).

When there is enough ATP and at the same time an excess of reduced coenzymes and oxygen, the respiratory chain can be uncoupled from the formation of ATP (uncoupling proteins - thermogenin  ). The electrochemical gradient of protons is thus used to generate heat. At the same time, however, complex III is inhibited by ATP so that energy is not wasted in this way. Triiodothyronine or Ca 2+ -dependent phosphorylation deactivates this mechanism of inhibition, which leads to an increase in energy output. This is how palmitate triggers thermogenesis in brown adipose tissue.

Other catabolic pathways are subordinate to the respiratory chain → they are inhibited by ↑ATP and ↑NADH+H + /NAD + and vice versa.

Regulation of the citrate cycle
Citrate cycle reactions are activated at ↓ATP/AMP and inhibited at ↑NADH+H + /NAD +, which subordinates the citrate cycle to the respiratory chain. In addition, the availability of the substrates: Ac-CoA and oxaloacetate (OAA) plays a role.

The main regulatory enzymes are:


 * citrate synthase – controlled by the availability of Ac-CoA and OAA   ;
 * isocitrate dehydrogenase and α-ketoglutarate dehydrogenase – controlled by the ratio of ATP/AMP and NADH+H + /NAD +.

Since citrate synthase is dependent on substrate availability, regulation is shifted to malate dehydrogenase (under respiratory control) and pyruvate carboxylase (or β-oxidation).

Other reactions of the citrate cycle can also be regulated: the enzyme aconitase blocks the poisonous fluoroacetate, malonate inhibits succinate dehydrogenase.

Regulation of pyruvate dehydrogenase
Pyruvate dehydrogenase (PDH) catalyzes the irreversible oxidative decarboxylation of pyruvate to Ac-CoA. Yippee:


 * inhibited – ↑NADH + H + /NAD +, ↑ATP/AMP so that pyruvate is not wasted when energy is not needed. It is also inhibited by its product, Ac-CoA, which is supposed to favor other sources of energy over glucose;
 * activated by postprandial insulin- induced dephosphorylation;
 * inhibited by phosphorylation – glucagon → ↑ cAMP → protein kinase A.

Regulation of glycolysis
The main regulatory element of glycolysis is 6-phosphofructo-1-kinase (catalyzes the conversion of Fru-6-P to Fru-1,6-PP). She is:


 * inhibited ↑ATP/AMP;
 * inhibited by citrate, resulting in a preference for lipids over glucose;
 * activated by insulin in the liver, inhibited by glucagon. There is no direct covalent modification of 6-phosphofructo-1-kinase, 6-phosphofructo-2-kinase is activated by dephosphorylation (as a result of insulin), which catalyzes the reaction: Fru-6-P + ATP ↔ ADP + Fru-2,6-PP, which acts as an activator of 6-phosphofructo-1-kinase. The opposite happens in the presence of glucagon;
 * inhibited by ↓pH, which protects the cell from being overwhelmed by lactate during anaerobic glycolysis, as it is accompanied by the release of H + ;

The second regulatory enzyme, pyruvate kinase, is controlled by the rate of Fru-1,6-PP formation and covalent modifications.

Regulation of gluconeogenesis
In the regulation of gluconeogenesis, the influence of the availability of substrates is applied. Gluconeogenesis regulatory enzymes are enzymes bypassing the irreversible reactions of glycolysis, i.e.:


 * pyruvate carboxylase : activated by ↑Ac-CoA – this is also an anaplerotic reaction of the citrate cycle;

The remaining regulatory enzymes are regulated by the same influences as glycolysis, only in the opposite way, and are activated by glucagon (cortisol) and inhibited by insulin.


 * PEP carboxykinase : activated ↑NADH+H + /NAD + ;
 * Fru-1,6-bisphosphatase : activated by citrate and starvation, inhibited by Fru-2,6-PP and AMP   ;
 * Glc-6-phosphatase

Glucocorticoids amplify the positive effect of glucagon on gluconeogenesis.

Regulation of glucose phosphorylation
Hexokinase, which is found in all tissues except the liver and β-cells of the pancreas , is inhibited by Glc-6-P and thus subordinate to other metabolic pathways.

Insulin results in the incorporation of GLUT-4 transporters into cell membranes and thus allows glucose to enter the tissues. Glucokinase found in the liver and β-cells of the pancreas is not affected by the concentration of Glc-6-P. Due to the high Km, its activity is dependent on the glucose concentration. It is activated by Fru-1-P (can lead to fatty liver ( steatosis ) due to excessive consumption of glucose along with fructose   ) and inhibited by Fru-6-P, which directs the resulting Glc-6-P to glycogen synthesis rather than to glycolysis.

GLUT-2 type transporters are found in liver cells and pancreatic β-cells, which are insulin-independent.

Regulation of glycogen metabolism
Regulation of glycogen metabolism is based on covalent modifications of enzymes.

Glucagon (especially in the liver) or catecholamines ( adrenaline, especially in the muscle) activate adenylate cyclase , resulting in ↑cAMP. The protein kinase-A (PKA) activated by it phosphorylates phosphorylase-kinase, which subsequently activates glycogen phosphorylase by phosphorylation. In addition, it can be activated via CaM-kinase as a result of ↑Ca 2+, which is manifested by an increase in the breakdown of glycogen during muscle work. PKA also deactivates glycogen synthase by phosphorylation.

In response to insulin, the opposite reactions occur. Protein phosphatase-1, which activates glycogen synthase by dephosphorylation and deactivates glycogen phosphorylase, is active at ↓cAMP.

Regulation of lipolysis, β-oxidation, ketogenesis
Hormone-sensitive lipase is activated by glucagon and catecholamines (via cAMP) and inhibited by insulin.

The rate of β-oxidation is primarily dependent on the rate of transfer of free fatty acids (FFA) to mitochondria. This transfer is ensured by carnitine-acyl transferase 1, which is inhibited by malonyl-CoA (an intermediate of fatty acid synthesis).

The regulation of ketogenesis is mainly subject to the availability of substrates and thus to the previous two processes. It also depends on the consumption of Ac-CoA by the hepatocyte.

Regulation of fatty acid synthesis
The main regulatory enzyme is Ac-CoA carboxylase (Ac-CoA → malonyl-CoA). Yippee:


 * activated by citrate - when the cell is in a good energy state, citrate escapes from the mitochondria and activates the production of fatty acids. At the same time, it inhibits glycolysis (see above), which leads to the use of glucose in the pentose cycle and the formation of reduced coenzymes NADPH+H + /, which are also needed in synthesis. Furthermore, citrate itself is a source of Ac-CoA;
 * inhibited by palmitoyl-CoA – slows down the synthesis of fatty acids if they do not have time to be esterified to TAG;
 * activated by insulin, deactivated by glucagon and catecholamines;
 * it is induced by a low-fat, energy-rich, high-carbohydrate diet.

The complex of fatty acid synthesis is regulated rather long-term, mainly by diet.

Regulation of TAG synthesis
TAG synthesis depends primarily on the availability of acyl-CoA. Thus, it is either subject to the synthesis of fatty acids, or to their supply from the circulation.

Lipoprotein lipase releases fatty acids from lipoproteins in adipose tissue, it is activated by insulin and apoprotein Apo-CII.

Regulation of the ornithine cycle
The regulatory enzyme of the ureosynthetic cycle is carbamoyl phosphate synthetase II. It is activated by N-acetylglutamate, which is synthesized from glutamate and Ac-CoA and increases with glutamate and arginine excess. Arginine comes mainly from the kidneys, where it was created from citrulline, which is synthesized from glutamine in the enterocytes during a rich protein diet.

Urea synthesis is also activated by the substrate, i.e. NH 3. On the other hand, an acidic pH leads to its inhibition, as the product is uric acid, which would further acidify the organism. This happens through inhibition of liver glutaminase. More ammonia is thus incorporated into glutamine by glutamine synthetase and excreted only in the kidneys.

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