Mechanisms of signaling and related enzymes

• Published in: Proteins, structure, function, and bioinformatics Vol. 29; no. 4; pp. 401 - 416
• Main Author: Mildvan, Albert S.
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01.12.1997
• Subjects: Animals; associative mechanisms; Catalysis; dissociative mechanisms; Enzymes - physiology; F1 ATPase; G proteins; Humans; Models, Molecular; myosin ATPase; nucleophilic substitution at phosphorus; phosphoserine-phosphothreonine protein phosphatases; phosphotyrosine protein phosphatases; protein kinases; Signal Transduction; Staphylococcal nuclease; transition-state structures; tyrosine kinases
• ISSN: 0887-3585; 1097-0134
• DOI: 10.1002/(SICI)1097-0134(199712)29:4<401::AID-PROT1>3.0.CO;2-B

Most enzymes involved in cell signaling, such as protein kinases, protein phosphatases, GTPases, and nucleotide cyclases catalyze nucleophilic substitutions at phosphorus. When possible, the mechanisms of such enzymes are most clearly described quantitatively in terms of how associative or dissociative they are. The mechanisms of cell signaling enzymes range from ≤8% associative (cAMP‐dependent protein kinase) to ≈50% associative (G protein Giα1). Their catalytic powers range from 105.7 (p21ras) to 1011.7 (λ Ser‐Thr protein phosphatase), usually comparable in magnitude with those of nonsignaling enzymes of the same mechanistic class. Exceptions are G proteins, which are 103‐ to 105‐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 in the case of p21ras, to the absence of a catalytic Arg residue, which interacts with the transition state. From kinetic studies of mutant and metal ion substituted enzymes, the catalytic powers of cell signaling and related enzymes can be rationalized quantitatively by factors contributed by metal ion catalysis (≥105), general acid catalysis (≈103±1), general base catalysis (≈103±1), and transition‐state stabilization by cationic and hydrogen bond donating residues (≈103±1). Proteins 29:401–416, 1997. © 1997 Wiley‐Liss, Inc.