MECHANISMS OF SIGNALING AND RELATED ENZYMES

Most enzymes involved in cell signaling, such as protein kinases, prot ein phosphatases, GTPases, and nucleotide cyclases catalyze nucleophil ic substitutions at phosphorus, When possible, the mechanisms of such enzymes are most clearly described quantitatively in terms of how asso ciative or dissociative they are, The mechanisms of cell signaling enz ymes range from less than or equal to 8% associative (cAMP-dependent p rotein kinase) to similar to 50% associative (G protein Gi alpha 1). T heir catalytic powers range from 10(5.7) (p21(ras)) to 10(11.7) (lambd a Ser-Thr protein phosphatase), usually comparable in magnitude with t hose of nonsignaling enzymes of the same mechanistic class, Exceptions are G proteins, which are 10(3)- to 10(5)-fold poorer catalysts than F1 and myosin ATPases, The lower catalytic powers of G proteins may be ascribed to the absence of general base catalysis, and additionally i n the case of p21(ras), to the absence of a catalytic Arg residue, whi ch interacts with the transition state, From kinetic studies of mutant and metal ion substituted enzymes, the catalytic powers of cell signa ling and related enzymes can be rationalized quantitatively by factors contributed by metal ion catalysis (greater than or equal to 10(5)), general acid catalysis (similar to 10(3+/-1)), general base catalysis (similar to 10(3+/-1)), and transition-state stabilization by cationic and hydrogen bond donating residues (similar to 10(3+/-1)). (C) 1997 Wiley-Liss, Inc.