Shemin cycle

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). 

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. 

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). 

These substances are synthesized from S-amino-levulinic acid formed in the Shemin cycle (p. 222). Two molecules of the acid are condensed to porphobilinogen, which is the precursor ring of the porph)rrin8. 

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

One obvious place to control porphyrin biosynthesis is to control the synthesis of 5-AL. This is the only step which requires a high enei bond in the form of succinyl-CoA. All the other steps involve reactions which are largely irrevermble and thermodynamically favored, such as the formation of a pyrrole ring, decarboxylation, and oxidation to the aromatic porphyrin ring. The rate of synthesis of 5-AL may be controlled by the amount of the enzyme 5-AL-f thetase, by the concentration of its coenzyme-pyridoxal phosphate, by the steady state level of succinyl-CoA and of glycine, and possibly by inhibitors of the enzyme such as cysteine. Once formed the 5-AL may be converted to porphyrin or may be oxidized via the Shemin cycle. It is difficult to obtain a quantitative estimate of the importance of this oxidative pathway (65, S91). 

Fio. 31. Distribution of the enzymes of heme biosyntbesis in the cell and hypothesis on the lesions in porphyria. If in acute porphyria S-AL-synthetase activity is enhanced as in chemical porphyria rather than that the Shemin cycle is blocked at (1) or the mitochondrion becomes permeable at (1) then i-AL will leak out, some will be converted to PBG, and both will be excreted. In congenital porphyria the PBG isomerase enzyme at (2) is decreased or damaged so UROGEN-I is formed and is in part transformed to COPROGEN-I, which are both excreted. 

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). 

Labeled glycine added to isolated intact reticulocytes from duck blood is converted to labeled heme as was first shown by Shemin et al. 20). In addition, PROTO is also formed (dS) and this compound can be determined directly by colorimetric methods. In chicken eiythrocytes supplied in vitro with excess glycine (0.05 M) about two-thirds of the newly formed porphyrin is in the form of PROTO and the rest is newly formed heme (S4)-Various members of the citric acid cycle also enhance the yield indicating that they are partially permeable to the red cell membrane 35). 

This normally requires the functioning ot a series of enzyme systems within the cell. The formation of succinyl CoA requires a citric acid cycle as shown by Shemin s tracer studies with succinate-1,4-C and succinate-2,3-C this was also shown by inhibition studies with malonate, trans-aconitate, fluoroacetate, or arsenite (35). Coupled to the citric acid cycle is an electron transfer system to O as shown by inhibition by CO and anaerobiosis. Inhibition by dinitrophenol su ests that oxidative phosphorylation is required, although dinitrophenol may inhibit 5-AL synthetase more directly (36). For AL synthesis, pyridoxal-P is required as shown by Schulman and Richert (37) on vitamin B -dehcient chicks and by inhibitors of pyridoxal-P, e.g., deoxypyridoxine, isonicotinic hydrazide, etc. (35). 

In erythrocytes the main pathway for succinyl CoA formation appears to be from a-ketoglutaric acid by oxidation via the citric acid cycle, through TPP and lipoic acid, to form succinyl lipoate which with CoA forms succinyl CoA. The conversion of succinate to succinyl CoA has been shown by Shemin and Kumin (38) who used labeled succinate in the presence of malonate. 

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). 

Shemin has pointed out that the oxidative deamination of aminolevulinate and the subsequent oxidation of ketoglutarate semialdehyde to ve ketoglutarate constitute a second cycle which would effect complete oxidation of glycine. The significance of this is still obscure. 

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