Transsulfuration sequence

Autotrophic organisms synthesize methionine from asparfafe as shovm in the lower right side of Fig. 24-13. This involves fransfer of a sulfur atom from cysfeine info homocysfeine, using the carbon skeleton of homoserine, the intermediate cystathionine, and two PLP-dependent enzymes, cystathionine y-synthase and cystathionine p-lyase. This transsulfuration sequence (Fig. 24-13, Eq. 14-33) is essentially irreversible because of the cleavage to pyruvate and NH4+ by the P-lyase. Nevertheless, this transsulfuration pathway operates in reverse in the animal body, which uses two different PLP enzymes, cystathionine P s3mthase (which also contains a bound heme) and cystathionine y-lyase (Figs. 24-13,24-16, steps h and i), in a pathway that metabolizes excess methionine. 

As noted above, cystathionine formation is the other major fate of methionine. The condensation of homocysteine with serine is catalyzed by the vitamin requiring enzyme cystathionine P-synthase. In the last step of the transsulfuration sequence, cystathionine undergoes cleavage to cysteine and a-ketobutyrate in yet another enzyme reaction that requires pyridoxal phosphate. 

While four domains of methionine synthase bind reaction components (HCY, SAM, cobalamin, and methylfolate), the fifth domain, known as the Cap domain, hovers above cobalamin while it is in its readily oxidized Cob(I) state, limiting access of reactive oxygen species or electrophilic substances. As such, the Cap domain restricts inactivation of methionine synthase and consequently promotes methylation over transsulfuration. In rt-PCR smdies using RNA from cultured human neuroblastoma cells, we found that the Cap sequence, corresponding to... 

Since methionine has several pathways open to it, it is essential to know what factors control the direction that its metabolism takes. Studies in young adults have shown that the utilization of methyl groups is normally accounted for chiefly by creatinine formation. This reaction consumes more 5-adenosylmethionine than all other transmethylations together. However, examination of enzyme activities from these two pathways in fetal animals leads to the conclusion that remethylation preponderates over transsulfuration. Indeed, since y-cystathionase activity is immeasurable in human fetal liver and brain, not only is the remethylation sequence favored, but also cysteine then becomes an essential amino acid for the fetus and infant. 

The transmethylation reaction, in which methionine is of major importance, has been described in the chapter on Enzymes in Metabolic Sequences (see p. 55), to which the reader may refer. The outstanding reaction involving methionine and cysteine to be discussed in this section is transsulfuration. 

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