Shemin pathway

The biosynthesis of all tetrapyrroles begins with the formation of ALA, which is the sole source of all carbon and nitrogen atoms required for the formation of the tetrapyrroie macrocycle. In nature, this small molecule is synthesized by two alternative, unrelated biosynthetic routes (Figure 3). In mammals, fungi, and the ct-group of proteobacteria ALA is formed via the condensation of succinyl-CoA and glycine, the so-called Shemin pathway named after one of the two discoverers, and is catalyzed by... 

Figure 3 Formation of 5-aminolevulinic acid. ALA is either synthesized from succinyl-CoA and glycine (Shemin pathway) or from the C5-skeleton of glutamate (C5-pathway).

One main interest in the study of 5-ALAD is its central position in the metabolism at the cross-road between the Shemin pathway and the Beale pathway leading to ALA, and the branched metabolism producing hemes and chlorophylls. Another interest is related to the evolution of energetics in radish seedlings from sowing, which depend, first of the differentiation of mitochondrias, and in later steps, of the development of chloroplasts, when the cotyledons have turned into leaves. 

Gabaculine-treated chlorophyll-deficient leaves respire normally, and there is normal cytochrome c oxidase in isolated mitochondria, providing evidence for the C5 pathway in plastids and the Shemin pathway in mitochondria and indicating the specific effect of gabaculine on the plastid... 

The first step of the heme biosynthetic pathway in mammalian cells involves the condensation of glycine with succinyl-coenzyme A (CoA) to yield 5-aminolevulinate (ALA), carbon dioxide and CoA (Figure 2-1). This reaction is catalyzed by ALA synthase (ALAS E.C. 2.3.1.37) and is considered to be the rate-limiting step in the production of heme in, at least, non-erythroid cells [1, 7, 8]. ALAS was initially discovered in the bacterimn Rhodobacter spheroides and in cMcken erythrocytes in the laboratories of Shemin [9] and Neuberger [10], respectively. However, it was not imtil the 1970s that the enzyme started to be isolated and purified from mammalian sources [11-13]. 

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). 

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. 

Early stages of the biosynthesis of tetrapyrrole compounds are inhibited by hemin and by the complete form of vitamin B12 (Lascels and Hatch, 1969 Vitamin B represses specifically its own synthesis (Bykhovsky et al., 1968, 1975a). The inhibiting effect of oxygen on vitamin Bn synthesis was attributed to the repression of ALA dehydratase and ALA synthase activities (Menon and Shemin, 1967), but now it is believed (Oh-hama et al., 1993) that in propionic acid bacteria ALA is formed in the C5 pathway. Bykhovsky... 

Studies on the chemical structure of chlorophyll showed that it was closely related to heme, a pigment found in mammalian tissue. Subsequent work has indicated that a common biosynthetic pathway exists for the synthesis of porphobilinogen, a precursor to these two pigments. The steps leading to the formation of porphobilinogen were worked out by Shemin and co-workers 0) in a series of brilliant tracer experiments. 

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. 

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). 

These observations drew attention to the pathways known to be concerned in the biosynthesis of porphyrins, a subject which has been reviewed by Shemin (87). The involvement of glycine and succinic acid 88, 89) in... 

---