A Caltech Library Service

Uniform binding and negative catalysis at the origin of enzymes

Noor, Elad and Flamholz, Avi I. and Jayaraman, Vijay and Ross, Brian L. and Cohen, Yair and Patrick, Wayne M. and Gruic-Sovulj, Ita and Tawfik, Dan S. (2022) Uniform binding and negative catalysis at the origin of enzymes. Protein Science, 31 (8). Art. No. e4381. ISSN 0961-8368. doi:10.1002/pro.4381.

[img] PDF - Published Version
Creative Commons Attribution.

[img] MS Word - Supplemental Material
Creative Commons Attribution.


Use this Persistent URL to link to this item:


Enzymes are well known for their catalytic abilities, some even reaching “catalytic perfection” in the sense that the reaction they catalyze has reached the physical bound of the diffusion rate. However, our growing understanding of enzyme superfamilies has revealed that only some share a catalytic chemistry while others share a substrate-handle binding motif, for example, for a particular phosphate group. This suggests that some families emerged through a “substrate-handle-binding-first” mechanism (“binding-first” for brevity) instead of “chemistry-first” and we are, therefore, left to wonder what the role of non-catalytic binders might have been during enzyme evolution. In the last of their eight seminal, back-to-back articles from 1976, John Albery and Jeremy Knowles addressed the question of enzyme evolution by arguing that the simplest mode of enzyme evolution is what they defined as “uniform binding” (parallel stabilization of all enzyme-bound states to the same degree). Indeed, we show that a uniform-binding proto-catalyst can accelerate a reaction, but only when catalysis is already present, that is, when the transition state is already stabilized to some degree. Thus, we sought an alternative explanation for the cases where substrate-handle-binding preceded any involvement of a catalyst. We find that evolutionary starting points that exhibit negative catalysis can redirect the reaction's course to a preferred product without need for rate acceleration or product release; that is, if they do not stabilize, or even destabilize, the transition state corresponding to an undesired product. Such a mechanism might explain the emergence of “binding-first” enzyme families like the aldolase superfamily.

Item Type:Article
Related URLs:
URLURL TypeDescription Information
Noor, Elad0000-0001-8776-4799
Flamholz, Avi I.0000-0002-9278-5479
Jayaraman, Vijay0000-0001-6288-1841
Cohen, Yair0000-0002-9615-2476
Patrick, Wayne M.0000-0002-2718-8053
Gruic-Sovulj, Ita0000-0002-3930-8323
Tawfik, Dan S.0000-0002-5914-8240
Additional Information:© 2022 The Authors. Protein Science published by Wiley Periodicals LLC on behalf of The Protein Society. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. Issue Online: 14 July 2022. Version of Record online: 14 July 2022. Manuscript accepted: 15 June 2022. Manuscript revised: 06 June 2022. Manuscript received: 01 March 2022. We are indebted to Lynn Kamerlin for her support throughout this difficult journey and John Richard for discussions about uniform binding. Prior to his death, Dan S. Tawfik wrote “I thank Wayne Patrick not only for introducing me to Albery and Knowles's concept of uniform binding, but also for doing so while guiding me through New Zealand's beautiful landscapes. I am grateful to Ita Gruic-Sovulj with whom I have endlessly discussed the validity and implications of uniform binding. I am indebted to my research group, and to Brian Ross in particular, for their insightful comments that were instrumental in refining this manuscript.” Financial support by The Volkswagen Foundation (Grant 94747) is gratefully acknowledged. Dan S. Tawfik was the incumbent of the Nella and Leon Benoziyo Professorial Chair. Elad Noor, Avi I. Flamholz, Vijay Jayaraman, and Brian L. Ross contributed equally to this study.
Funding AgencyGrant Number
Volkswagen Foundation94747
Nella and Leon Benoziyo Professorial ChairUNSPECIFIED
Subject Keywords:enzyme evolution; negative catalysis; primordial catalys;t substrate-handle; triose phosphate isomerase; uniform binding
Issue or Number:8
Record Number:CaltechAUTHORS:20220714-369203000
Persistent URL:
Official Citation:Noor, E, Flamholz, AI, Jayaraman, V, Ross, BL, Cohen, Y, Patrick, WM, et al. Uniform binding and negative catalysis at the origin of enzymes. Protein Science. 2022; 31( 8):e4381.
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:115543
Deposited By: George Porter
Deposited On:14 Jul 2022 22:56
Last Modified:14 Jul 2022 22:56

Repository Staff Only: item control page