Glycine-Succinate Cycle

Activated succinate see IHcarboxylic acid cycle. Succinate-glycine cycle. Fatty acid degradation. 

Aminolevulhiic add. S-amiHolevullnic acid, ALA an intermediate in porphyrin biosynthesis, and part of the Shemin cycle (see Succinate-glycine cycle). ALA is biosynthesi d by at least two distinct pathways, which are described in Porphyrins (see). 

Glycine-succinate cycle see Succinate-glycine cycle. 

Succinate-glycine cycle, glycine-succinate cycle, Shemin cycle a bypass of the TCA-cycle of particular importance in the metabolism of red blood cells. It converts succinyl-CoA and glycine into 5-aminolevu-linate, which is the biosynthetic precursor of the Porphyrins (see). Alternatively, 5-aminolevulinate is de-aminated to 2-oxoglutarate semialdehyde, and the cycle is completed by formation of succinyl-CoA via 2-oxoglutarate. One turn of the cycle converts glycine into 2 molecules CO2 and 1 molecule NHj. 2-Oxoglu-tarate semialdehyde can also be converted into succinate and a Cl-unit. 

The fate of 5-amino levulinic acid is dual. It may be converted to porphobilinogen by a pathway to be described below, or under the influence of a transaminase it may yield a-ketoglutaraldehyde, which in turn produces a-ketoglutarate or succinate (see Fig. 3-50). Thus, 5-amino levulinic acid occupies a key position between the citric acid cycle and the porphyrins biosynthetic pathway. The significance of 5-amino levulinic acid in metabolism is illustrated in Fig. 3-50 showing the metabolic conversions involved in the so-called Shemin succinate glycine cycle. 

Shemin, D. The succinate-glycine cycle The role of -aminolevulinic acid in porphyrin synthesis. In Porphyrin biosynthesis and metabolism (Wolstenholme, G.E.W., and Millar, E.C.P., eds.). Proc. Ciba Symp., p. 4-22. Poston Little, Brown and Company 1955... 

Reactions in which a succinate group derived from a-ketoglutarate condenses with glycine to initiate a succinate glycine cycle have been reviewed by D. Shemin, Federation Proc. 16, 971 (1956). 

The respiratory CO2 produced from the ycine-2-C , however, was found to be twenty-five times more radioactive than that from the aminolevulinic acid. This result emphasizes that glycine is not metabolized exclusively via the succinate-glycine cycle. In fact, on the basis of this figure this may represent only a minor pathway. 

Scheme 4). This unexpected enrichment of two neighboring carbons from a single-labeled precursor can be explained by assuming that labeled glycine was introduced into TCA cycle via malate. In the cycle, the molecular asymmetricity will be lost at the succinate step, and the labeling will appear on both C-2 and C-3 of succinate. The result seems to support Scheme Ic, since C-4 and C-3 of glutamate correspond to C-11 and C-12 of the toxin molecule in such a scheme. 

One important point about Figure 2.6 is that some amino acids have two connection points with the citric acid cycle. The four amino acids involved are all degraded to more than one end product. L-Threonine is broken down to glycine plus acetyl CoA, whilst isoleucine yields acetyl CoA plus succinate. Both phenylalanine and tyrosine produce oxalacetate plus acetyl CoA. Tryptophan has a unique metabolism of its own [84]. 

Knowledge of the building blocks of protoporphyrin (more specifically of iron protoporphyrin) is derived primarily from recent tracer studies (see below). The results of the tracer studies indicate that the porphyrin molecule is built up of eight glycine and eight 4-carbon units. The specific 4-carbon unit is as yet unidentified it appears to be an intermediate of the citric-acid cycle (or derived from an intermediate)— possibly an intermediate between a-ketoglutarate and succinic acid. 

But this is not the only entry of glycine into the priming reactions. Glycine can be converted into CO, and water by means of the Shemin cycle, where the catalyst is not oxaloacetate as in the Krebs cycle, but succinate, whose active form, succinyl-CoA, condenses with the ydne. The Shemin cycle can therefore be worked into that of Krebs to form a shunt (Fig. 54). 

The succinyl-CoA condenses with glycine, at the a-carbon atom, to form a-amino-j8-ketoadipic acid which is then decarboxylated to S-amino-levulinic acid. The latter is deaminated to ketoglutaraldehyde which is oxidized to ketoglutaric add. This compound enters the tricarboxylic acid cycle or is decarboxylated to succinic acid. In one revolution of the cycle one molecule of glycine is completely oxidized to CO, and water. 

Fia. 1. Glycine catabolism pathway 1, via serine and pyruvate pathway 2, via glyoxylic acid and formate pathway 3, via the glycine-succinate cycle. 

It was proposed by Shemin and Russell ( 9) that 5-AL not only gave rise to porphyrins but could be oxidized back to succinic acid. This would provide an alternate path for glycine oxidation. It is difficult to obtain a quantitative idea of the amount of 5-AL that is decomposed via this cycle. Experiments from Neuberger s laboratory (391) suggested that perhaps 30 % of the 5-AL formed may undergo oxidation. The complex relation of glycine metabolism and porphyrin synthesis has recently been carefully analyzed by Neuberger (55). 

Evidence for this cycle (Fig. 10) was provided by Nemeth et al. (56). When 5-AL was labeled in the C-5 position (i.e., derived from the a-carbou of glycine) and injected into the duck, the 0 -5 atom was incorporated into the ureido groups of purines in red blood cells and was also excreted as formic acid. Injection into rats of 5-AL labeled in the C-1 and C-4 atoms together with malonate led to excretion in the urine of succinate labeled only in carboxyl groups. Injection of y-ketoglutaraldehyde-5-C into the rat led... 

Fio. 10. The Shemin cycle for glycine oxidation with succinate as catalyst (t9). 

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