NADH/NAD+ ratio

High NADH/NAD+ ratio High AcCoA/CoASH ratio... 

The second electron shuttle system, called the malate-aspartate shuttle, is shown in Figure 21.34. Oxaloacetate is reduced in the cytosol, acquiring the electrons of NADH (which is oxidized to NAD ). Malate is transported across the inner membrane, where it is reoxidized by malate dehydrogenase, converting NAD to NADH in the matrix. This mitochondrial NADH readily enters the electron transport chain. The oxaloacetate produced in this reaction cannot cross the inner membrane and must be transaminated to form aspartate, which can be transported across the membrane to the cytosolic side. Transamination in the cytosol recycles aspartate back to oxaloacetate. In contrast to the glycerol phosphate shuttle, the malate-aspartate cycle is reversible, and it operates as shown in Figure 21.34 only if the NADH/NAD ratio in the cytosol is higher than the ratio in the matrix. Because this shuttle produces NADH in the matrix, the full 2.5 ATPs per NADH are recovered. 

Theoretically, a fall in concentration of oxaloacetate, particularly within the mitochondria, could impair the ability of the citric acid cycle to metabolize acetyl-CoA and divert fatty acid oxidation toward ketogenesis. Such a fall may occur because of an increase in the [NADH]/[NAD+] ratio caused by increased P-oxida-tion affecting the equilibrium between oxaloacetate and malate and decreasing the concentration of oxaloacetate. However, pyruvate carboxylase, which catalyzes the conversion of pyruvate to oxaloacetate, is activated by acetyl-CoA. Consequently, when there are significant amounts of acetyl-CoA, there should be sufficient oxaloacetate to initiate the condensing reaction of the citric acid cycle. 

Alcohol metabolism increases the NADH/NAD ratio in the cytoplasm. 

Alcoholics can also develop ketoaddosis. In alcoholic ketoacidosis, 3-hydroxybutyrate is the major ketone body produced because there is usually a high NADH/NAD ratio in the hver. The urinary nitroprusside test detects only acetoacetate and may dramatically underestimate the extent of ketosis in an alcoholic. 3-Hydroxybutyrate levels (P-hydroxybutyrate) should always be measured in these patients. 

Ethanol oxidation, via alcohol dehydrogenase, reduces testosterone secretion, due to a high NADH/NAD ratio is the Leydig cells in the testes. 

The most important factor in the regulation of the cycle is the NADH/NAD ratio. In addition to pyruvate dehydrogenase (PDH) and oxoglu-tarate dehydrogenase (ODH see p. 134), citrate synthase and isodtrate dehydrogenase are also inhibited by NAD deficiency or an excess of NADH+HT With the exception of isocitrate dehydrogenase, these enzymes are also subject to product inhibition by acetyl-CoA, suc-cinyl-CoA, or citrate. 

In addition, cofactor engineering has been used to deliberately modify the intracellular NADH/NAD+ ratio that plays a predominant role in controlling the Lactococcus lactis fermentation pattern. The introduction of the nox gene, which codes for a NADH oxidase (NOX) that converts molecular oxygen to water at the expense of NADH, to a strain with an inactivated copy of the aldB gene for a-acetolactate decarboxylase led to the efficient metabolism of the na-... 

The result of formate accumulation is metabolic acidosis. However, at later stages, the acidosis may also involve the accumulation of other anions such as lactate. This may be a result of inhibition of cytochrome oxidase and hence of mitochondrial respiration, tissue hypoxia due to reduced circulation of blood, or an increase in the NADH/NAD ratio. The acidosis that results from methanol poisoning will result in more formic acid being in the nonionized state and hence more readily able to enter the CNS. This will cause central depression and hypotension and increased lactate production. This situation is known as the "circulus hypoxicus."... 

There is a logic to the route of these reactions through the mitochondrion. The [NADH]/[NAD+] ratio in the cytosol is 8 X 10 4, about 105 times lower than in mitochondria. Because cytosolic NADH is consumed in gluconeogenesis (in the conversion of 1,3-bisphos-... 

An excellent general discussion of the importance of the [NADH]/[NAD+] ratio in cellular regulation. 

Two of the enzymes of /3 oxidation are also regulated by metabolites that signal energy sufficiency. When the [NADH]/[NAD+] ratio is high, /3-hydroxyacyl-CoA dehydrogenase is inhibited in addition, high concentrations of acetyl-CoA inhibit thiolase (Fig. 17-12). 

Individuals with either type of diabetes are unable to take up glucose efficiently from the blood recall that insulin triggers the movement of GLUT4 glucose transporters to the plasma membrane of muscle and adipose tissue (see Fig. 12-8). Another characteristic metabolic change in diabetes is excessive but incomplete oxidation of fatty acids in the liver. The acetyl-CoA produced by JS oxidation cannot be completely oxidized by the citric acid cycle, because the high [NADH]/[NAD+] ratio produced by JS oxidation inhibits the cycle (recall that three steps convert NAD+ to NADH). Accumulation of acetyl-CoA leads to overproduction of the ketone bodies acetoacetate and /3-hydroxybutyrate, which cannot be used by extrahepatic tissues as fast as they are made in the liver. In addition to /3-hydroxybutyrate and acetoacetate, the blood of diabetics also contains acetone, which results from the spontaneous decarboxylation of acetoacetate ... 

Effect of [NADH]/[NAD+] on the Citric Acid Cycle How would you expect the operation of the citric acid cycle to respond to a rapid increase in the [NADH]/[NAD+] ratio in the mitochondrial matrix Why ... 

Niacin ia a nutritional term applied to both nicotinic acid and nicotinamide and to a mixture of the two. Their structures and those of their coenzymes are given in Table 6.1. Numerous redox reactions use NAD+ and NADP+ or NADH and NADPH. The latter are used largely in reactions designed to reductively synthesize various substances, mostly in the extramitochondrial areas of the cell. NAD+, on the other hand, is used largely in its oxidized form in catabolic redox reactions. The rat liver cytosol NADPH/NADP+ ratio is about 80, whereas its NADH/NAD+ ratio is only 8 x 10 4. Table 6.3 lists some biochemical reactions in which these cofactors participate. It shows that they are of crucial importance in the metabolism of carbohydrates, fats, and amino acids. 

Hence, if either the ratios of acetyl-CoA/CoA or NADH/NAD+ were high, it would be advantageous to render the PDHC inactive. There are three ways in which this is achieved the kinase is active (1) when the NADH/NAD+ ratio is high (2) active when the acetyl-CoA/CoA ratio is high and (3) the phosphatase is inhibited when the ratio of NADH/NAD+ is high. Thus, the portion of the PDHC that is active is sensitive to the metabolic requirements of the cell. 

The equilibrium constant for this reaction is known from in vitro studies. How could this be used to calculate the cytosolic NADH/NAD+ ratio ... 

A rise in the NADH/NAD ratio and the associated increase in the redox potential as well as the formation of acetaldehyde result in a variety of metabolic disturbances in the hepatocellular oxidation processes, so that pathophysiological consequences can be observed. This large variety of alcohol-induced metabolic disturbances is responsible for many situations of clinical importance, and thus acute and chronic alcohol abuse will eventually result in additional metabolic complications, (s. tab. 28.2)... 

E) stimulation of the flux through a number of enzymes by a decreased NADH/NAD+ ratio... 

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