Metabolic Fates Of Pyruvate Nasib Piruvat, Lactate & Etanol Metabolisme

Pyruvate is the branch point molecule of glycolysis. The ultimate fate of pyruvate depends on the oxidation state of the cell. In the reaction catalyzed by G3PDH a molecule of NAD⁺ is reduced to NADH. In order to maintain the re-dox state of the cell, this NADH must be re-oxidized to NAD⁺.

During aerobic glycolysis this occurs in the mitochondrial electron transport chain generating ATP. Thus, during aerobic glycolysis ATP is generated from oxidation of glucose directly at the PGK and PK reactions as well as indirectly by re-oxidation of NADH in the oxidative phosphorylation pathway. Additional NADH molecules are generated during the complete aerobic oxidation of pyruvate in the TCA cycle. Pyruvate enters the TCA cycle in the form of acetyl-CoA which is the product of the pyruvate dehydrogenase reaction. The fate of pyruvate during anaerobic glycolysis is reduction to lactate.

Lactate Metabolism

During anaerobic glycolysis, that period of time when glycolysis is proceeding at a high rate (or in anaerobic organisms), the oxidation of NADH occurs through the reduction of an organic substrate. Erythrocytes and skeletal muscle (under conditions of exertion) derive all of their ATP needs through anaerobic glycolysis. The large quantity of NADH produced is oxidized by reducing pyruvate to lactate. This reaction is carried out by lactate dehydrogenase, (LDH). The lactate produced during anaerobic glycolysis diffuses from the tissues and is transproted to highly aerobic tissues such as cardiac muscle and liver. The lactate is then oxidized to pyruvate in these cells by LDH and the pyruvate is further oxidized in the TCA cycle. If the energy level in these cells is high the carbons of pyruvate will be diverted back to glucose via the gluconeogenesis pathway.

Mammalian cells contain two distinct types of LDH subunits, termed M and H. Combinations of these different subunits generates LDH isozymes with different characteristics. The H type subunit predominates in aerobic tissues such as heart muscle (as the H4 tetramer) while the M subunit predominates in anaerobic tissues such as skeletal muscle as the M4 tetramer). H4 LDH has a low K_m for pyruvate and also is inhibited by high levels of pyruvate. The M4 LDH enzyme has a high K_m for pyruvate and is not inhibited by pyruvate. This suggsts that the H-type LDH is utilized for oxidizing lactate to pyruvate and the M-type the reverse.

Etanol Metabolisme

Acetaldehyde forms adducts with proteins, nucleic acids and other compounds, the results of which are the toxic side effects (the hangover) that are associated with alcohol consumption. The ADH and AcDH catalyzed reactions also leads to the reduction of NAD⁺ to NADH. The metabolic effects of ethanol intoxication stem from the actions of ADH and AcDH and the resultant cellular imbalance in the NADH/NAD⁺. The NADH produced in the cytosol by ADH must be reduced back to NAD⁺ via either the malate-aspartate shuttle or the glycerol-phosphate shuttle. Thus, the ability of an individual to metabolize ethanol is dependent upon the capacity of hepatocytes to carry out eother of these 2 shuttles, which in turn is affected by the rate of the TCA cycle in the mitochondria whose rate of function is being impacted by the NADH produced by the AcDH reaction. The reduction in NAD⁺ impairs the flux of glucose through glycolysis at the glyceraldehyde-3-phosphate dehydrogenase reaction, thereby limiting energy production. Additionally, there is an increased rate of hepatic lactate production due to the effect of increased NADH on direction of the hepatic lactate dehydrogenase (LDH) reaction. This reverseral of the LDH reaction in hepatocytes diverts pyruvate from gluconeogenesis leading to a reduction in the capacity of the liver to deliver glucose to the blood.

In addition to the negative effects of the altered NADH/NAD⁺ ratio on hepatic gluconeogenesis, fatty acid oxidation is also reduced as this process requires NAD⁺ as a cofactor. In fact the opposite is true, fatty acid synthesis is increased and there is an increase in triacylglyceride production by the liver. In the mitocondria, the production of acetate from acetaldehyde leads to increased levels of acetyl-CoA. Since the increased generation of NADH also reduces the activity of the TCA cycle, the acetyl-CoA is diverted to fatty acid synthesis. The reduction in cytosolic NAD⁺ leads to reduced activity of glycerol-3-phosphate dehydrogenase (in the glcerol 3-phosphate to DHAP direction) resulting in increased levels of glycerol 3-phosphate which is the backbone for the synthesis of the triacylglycerides. Both of these two events lead to fatty acid deposition in the liver leading to fatty liver syndrome.

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