Tricarboxylic acid cycle fumarate production

Oxidation may take place by a modified tricarboxylic acid cycle in which the production of CO2 is coupled to the synthesis of NADPH and reduced ferredoxin, and the dehydrogenation of succinate to fumarate is coupled to the synthesis of reduced menaquinone. This pathway is used, for example, by Desulfuromonas acetoxidans and in modified form by... 

Evidence suggests that elevated levels of the tricarboxylic acid cycle intermediates fumarate and succinate (the latter a product of hydroxylase catalysis) in some tumors may lead to activation of the HIF system via hydroxylase inhibition (97,98). Both succinate and fumarate are PHD2 inhibitors competing with 20G for binding to Fe(II) (99, 100). 

The production of L-malic acid (2) from fumaric acid (1) is carried out by the enzyme fumarate hydratase (E.C. 4.2.1.2), which is part of the tricarboxylic acid cycle and ubiquitous in nature (Scheme 11.5-1). The product is used in food, pharmaceutical and cosmetic industries and is produced at a multi-ten-tonne scale. Although the enzyme can be applied in isolated form, as performed by Tanabe, the use of whole cells of Corynebacterium glutamicum has been reported by Amino GmbH as well141. 

The aspartate entering the cycle is produced by reaction of glutamate with ox-alacetate, the former being produced from a-ketoglutarate plus ammonia released by deamination of an amino acid. The oxalacetate is derived from the fumarate released in the production of arginine from ai inosuccinate, which enters the tricarboxylic acid cycle and is converted to malate and then oxalacetate. We then have a second associated cycle linking the luea and the tricarboxylic acid cycles, which may be visualised as shown in Fig. 9.13. 

Now, with aspartate (Asp, D) in hand, for example, it should be clear that transamination will allow production of both essential and nonessential amino adds. Alanine (Ala, A), as shown in Scheme 12.2, can be formed when pyruvate (derived, e.g., from phosphoenolpyruvate via 2-phosphoglycerate, as shown inter alia Scheme 11.25) undergoes transamination from aspartate (Asp, D) (produced as in Equation 12.3 from fumarate). Fumarate, it will be remembered (Scheme 11.89), is produced in the tricarboxylic acid cycle. So, as shown in Scheme 12.2, the aminotransferase cofactor, pyridoxal, serves to deaminate aspartate (Asp, D) to produce oxaloacetate. The amino group is then transferred to pyruvate to yield alanine (Ala, A) and the pyridoxal cofactor is regenerated. ... 

COs to form oxalacetate which under anaerobic conditions is reduced to malate. The malate in turn may be converted to fumarate and succinate (Fig, 5). The last step in this series of reactions is blocked by malonate. The second pathway involves the aerobic condensation of pyruvate and oxalacetate followed by oxidation of the condensation product to form -ketoglutarate and succinate. Wood has proposed that the first condensation product of the aerobic tricarboxylic cycle is cfs-aconitic acid which is then converted to succinate by way of isocitric, oxalosuccinic, and a-ketoglutaric acids. The a-ketoglutarate is decarboxylated and oxidized to succinic acid. Isotopic a-ketoglutarate containing isotopic carbon only in the carboxyl group located a to the carbonyl would be expected to yield non-isotopic succinate after decarboxylation. This accounts for the absence of isotopic carbon in succinate isolated from malonate-poisoned liver after incubation with pyruvate and isotopic bicarbonate. 

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