Krebs cycle, intermediates

As simple examples of the approach, let us consider the amino acid (—)-serine and the Krebs cycle intermediate (+)-malic acid. 

The Krebs cycle intermediate that reacts with acetyl-CoA is oxaloacetate, and this reacts via an aldol reaction, giving citryl-CoA. However, the enzyme citrate synthase also carries out hydrolysis of the thioester linkage, so that the product is citrate hence the terminology citric acid cycle . The hydrolysis of the thioester is actually responsible for disturbing the eqnilibrinm and driving the reaction to completion. 

GABA acts as an inhibitory transmitter in many different CNS pathways. It is subsequently destroyed by a transamination reaction (see Section 15.6) in which the amino group is transferred to 2-oxoglutaric acid, giving glutaric acid and succinic semialdehyde. This also requires PLP as a cofactor. Oxidation of the aldehyde group produces succinic acid, a Krebs cycle intermediate. 

Decarboxylation of a-ketoacids such as pyruvate and a-ketoglutarate for the production of TCA or Krebs cycle intermediates ... 

Insects poisoned with rotenone exhibit a steady decline in oxygen consumption and the insecticide has been shown to have a specific action in interfering with the electron transport involved in the oxidation of reduced nicotinamide adenine dinudeotide (NADH) to nicotinamide adenine dinucleotide (NAD) by cytochrome h. Poisoning, therefore, inhibits the mitochondrial oxidation of Krebs-cycle intermediates which is catalyzed by NAD. 

Vitamin B12 is essential for the methylmalonyl-CoAmutase reaction. Methylmalonyl-CoA mutase is required during the degradation of odd-chain fatty acids and of branched-chain amino acids. Odd-chained fatty acids lead to propionyl-CoA as the last step of P-oxida-tion. Methylmalonyl-CoA can be derived from propionyl-CoA by a carboxylase reaction similar to that of fatty acid biosynthesis. The cofactor for this carboxylation reaction is biotin, just as for acetyl-CoA carboxylase. The reaction of methylmalonyl-CoA mutase uses a free radical intermediate to insert the methyl group into the dicar-boxylic acid chain. The product is succinyl-CoA, a Krebs cycle intermediate. The catabolisms of branched-chain lipids and of the branched-chain amino acids also require the methylmalonyl-CoA mutase, because these pathways also generate propionyl-CoA. 

Krebs cycle intermediates (Table 5.12) and/or enzymes (Table 5.13). Nevertheless, certain key enzymes, especially aconitase and isocitrate dehydrogenase, are very low in activity or are undetectable in species such as H. diminuta, whereas only very small amounts of 14C02, a characteristic end-product of the TCA cycle, were liberated in vitro from [14C]glucose by the tetrathyridia of Mesocestoides corti (399) and adults of Cotugnia digonopora (618). The classical TCA cycle is, therefore, unlikely to function to any significant extent in these cestodes. 

The acetyl CoA that gets on the ferris wheel can be continually replenished through glucose breakdown, or, mainly, through fatty acid degradation (oxidation), or by transformation of certain amino acids. What, however, produces the seats of the ferris wheel, or replenishes them when necessary The seats cannot be replaced by acetyl CoA, which is merely a passenger. The chemicals of the ferris wheel can be restored in part by certain amino acids that can convert to Krebs cycle intermediates. There also is an important side step in which pyruvate can be directly convert to oxaloacetate (D-8). 

Harold Morowitz (1999 Chapter 18, this volume), have vigorously defended the theory that life started from scratch in autotrophic fashion. Their proposed schemes differ, but have in common that they attribute a central role to a reverse, reductive Krebs cycle, from which the first amino acids would have arisen by amination of certain intermediates. A recent cladistic analysis has, however, led to the opposite conclusion that Krebs-cycle intermediates arose from amino acids by deamination (Cunchillos and Lecointre, 2002). 

Interestingly, the number of examples of toxicity biomarkers discovered using nuclear magnetic resonance (NMR)-based and MS-based metabonomics is quite impressive. In metabonomics studies in which a severe toxicity is observed, almost always the relative urinary concentrations of Krebs cycle intermediates are decreased and a concomitant decrease in urinary levels of hippuric acid is observed. These compounds have been proposed to be nonspecific markers of toxicity as they reflect a combination of complex changes in an organism [11,48-51], Taurine has been known to be a specific marker for liver toxicity as its urinary levels are typically increased with necrosis and fatty liver. Several bile acids in the serum such as cholic, glycolic, and taurocholic acids have also been demonstrated to be sensitive markers of liver dysfunction [50], In the literature, there are a few preclinical and clinical examples of... 

Assuming that no Krebs cycle intermediates are lost or gained, their levels will remain constant, the CO2 given off being derived from acetyl CoA (from pyruvate). 

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