Kinetics, methionine synthase

Banerjee, R. V., Frasca, V., Ballou, D. P, and Matthews, R. G., 1990, Participation of cob(I)alamin in the reaction catalyzed by methionine synthase from Escherichia colt a steady-state and rapid kinetic analysis. Biochemistry 29 11101nlll09. 

It is fascinating that a covalent tether to the Bn domain is needed for activation to proceed (9). The loss of translational freedom resulting from fusion of the domains thus appears to be an important feature of the cap-on activation-on conversion. The contraints on other domain movements conferred by linkers may play an important role in the overall energetics and kinetics of methionine synthase. 

The metabolic control of methionine metabolism is complex and involves, for example, changes of enzyme levels in particular tissues, mechanisms linked to the kinetic properties of the various enzymes and their interaction with metabolic effectors [6, 7]. A particularly important metabolic effector is AdoMet. This inhibits the low Km isoenzymes of MAT, and MTHF reductase, inactivates betaine methyltransferase, but activates MAT III (the high-Km isoenzyme) and cystathionine /1-synthase. Therefore, high methionine intake and thus higher AdoMet levels favour trans-sulphuration, and when levels are low methionine is conserved. AdoHcy potently inhibits AdoMet-dependent methyltransferases and both Hey remethylating enzymes. Another important control mechanism is the export of Hey from cells into the extracellular space and plasma, which occurs as soon as intracellular levels increase [8]. 

A second metabolic system similar to the first is shown in Figure 1, panel ii. In this schematic, the emphasis is a metabolite one or two steps proximal to the primary enzyme deficiency. For example, in normal individuals, metabolite C is converted by enzyme Y to metabolite A, which is subsequently converted by enzyme X to metabolite B. As described above, in individuals with an inherited deficiency of enzyme X, metabolite A accumulates. In this particular scenario, compounds that are converted to metabolite A, namely metabolite C, will increase as enzyme Y is inhibited by basic kinetics. An example of this enzyme system is homocystinuria. In this disorder, the metabolism of homocysteine to cystathionine by cystathionine S-synthase is blocked. An increase in homocysteine causes an accumulation of S-adenosyl homocysteine and S-adenosyl methionine. Due to an increase in these metabolites, the metabolism of methionine to S-adenosyl methionine by methionine adenosyl transferase is decreased. Hence, methionine increases in the blood of individuals with homocystinuria. Note that in this example there were two enzymatic steps before the metabolism of homocysteine. 

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