Regulatory Enzymes Occupy Key Positions in Pathways

Enzymes that are susceptible to direct regulation occupy key positions in metabolic pathways. In a multistep pathway the first enzyme in the pathway is usually regulated, and the others are not (fig. 11,8a). In the case of CTP synthesis (see chapter 9), we saw that the enzyme aspartate car- 

Branchpoints in metabolic pathways sometimes occur at locations where an intermediary, S, can follow a catabolic sequence or an anabolic sequence. The first reactions after the branchpoints are catalyzed by enzymes B and A, respectively. Once the first step after the branchpoint has been taken, the metabolic intermediate is irreversibly committed to follow that pathway. 

The mechanism is clearly flexible and economical. If there is sufficient end product, there is no point in processing substrates down the pathway. To do so is a waste of both energy and materials. Furthermore, it is most effective to block the first enzyme in the pathway this by itself rapidly reduces activity of the entire pathway. It is redundant to block any other enzymes in the pathway, because no intermediates are available to these enzymes if the first step is blocked. Blocking a middle enzyme in the pathway, instead of the first enzyme, also is quite wasteful. The result is accumulation of an intermediate that serves no useful function. Indeed, such intermediates in excess frequently have harmful effects. 

In a branched-chain anabolic pathway, end-product inhibition usually regulates the first enzyme after the branchpoint (fig. I l, 8b). This arrangement leads to control of either pathway after the branchpoint (fig. 11.8b). If the supply of the branchpoint substrate (D in fig. 11.8b) is limiting, the inhibition of one pathway after the branchpoint can increase the metabolic flow of the other pathway. This effect is often highly significant. Apropos of this point, anabolic sequences frequently arise as branchpoints from catabolic pathways (fig. 11.9). In such instances the control factors affect whether a catabolic intermediate is further degraded or serves as a substrate for biosynthesis. 

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