Understanding enzyme superfamilies. Chemistry as the fundamental determinant in the evolution of new catalytic activities

Patricia C. Babbitt, John A. Gerlt

Research output: Contribution to journalShort survey

Abstract

We have described four superfamilies of enzymes where the members within each catalyze different overall reactions using broadly varied substrates. Within each superfamily, the different overall reactions are facilitated by a common mechanistic strategy that can be rationalized in the context of the structural scaffold. Although space limitations prevent their discussion, a number of additional superfamilies have been described in which these principles appear to obtain. Analyses of the relationships between structure and function in all of these superfamilies suggest two general conclusions regarding the evolution of new catalytic activities. 1) Nature discovered that chemistry, and not binding specificity, is the dominant factor in the evolution of new enzymatic activities. New enzymatic activities evolve by duplication of the gene for a preexisting enzyme that provides a structural strategy for a mechanistically difficult chemical step. As a result, related enzymes can differ broadly in the identity of the overall reactions they mediate as well as in substrate specificity. 2) The catalytic activity of a newly sequenced but uncharacterized open reading frame cannot necessarily be inferred from the overall reactions catalyzed by homologous enzymes. Rather, the chemical step common to the superfamily scaffold must be identified and correlated with conserved structural features. These conclusions should be useful in developing new strategies for solving problems of current interest in mechanistic enzymology and structural biology as well as in the emerging disciplines of bioinformatics. For example, determination of the principles that govern the structure-function correlations for any particular superfamily will likely play an important role in assigning catalytic function to unknown sequences. Finally, by providing a more contextual basis for understanding both the rapid rates and mechanisms of enzyme-catalyzed reactions, superfamily analysis has the potential to offer insights that cannot be obtained even from the most elegant studies of a single enzyme.

Original languageEnglish (US)
Pages (from-to)30591-30594
Number of pages4
JournalJournal of Biological Chemistry
Volume272
Issue number49
DOIs
StatePublished - Dec 5 1997

Fingerprint

Catalyst activity
Enzymes
Scaffolds
Gene Duplication
Substrates
Bioinformatics
Substrate Specificity
Computational Biology
Open Reading Frames
Genes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Understanding enzyme superfamilies. Chemistry as the fundamental determinant in the evolution of new catalytic activities. / Babbitt, Patricia C.; Gerlt, John A.

In: Journal of Biological Chemistry, Vol. 272, No. 49, 05.12.1997, p. 30591-30594.

Research output: Contribution to journalShort survey

@article{ebf48fc5df4c4469a9a58c4cfee9ddb6,
title = "Understanding enzyme superfamilies. Chemistry as the fundamental determinant in the evolution of new catalytic activities",
abstract = "We have described four superfamilies of enzymes where the members within each catalyze different overall reactions using broadly varied substrates. Within each superfamily, the different overall reactions are facilitated by a common mechanistic strategy that can be rationalized in the context of the structural scaffold. Although space limitations prevent their discussion, a number of additional superfamilies have been described in which these principles appear to obtain. Analyses of the relationships between structure and function in all of these superfamilies suggest two general conclusions regarding the evolution of new catalytic activities. 1) Nature discovered that chemistry, and not binding specificity, is the dominant factor in the evolution of new enzymatic activities. New enzymatic activities evolve by duplication of the gene for a preexisting enzyme that provides a structural strategy for a mechanistically difficult chemical step. As a result, related enzymes can differ broadly in the identity of the overall reactions they mediate as well as in substrate specificity. 2) The catalytic activity of a newly sequenced but uncharacterized open reading frame cannot necessarily be inferred from the overall reactions catalyzed by homologous enzymes. Rather, the chemical step common to the superfamily scaffold must be identified and correlated with conserved structural features. These conclusions should be useful in developing new strategies for solving problems of current interest in mechanistic enzymology and structural biology as well as in the emerging disciplines of bioinformatics. For example, determination of the principles that govern the structure-function correlations for any particular superfamily will likely play an important role in assigning catalytic function to unknown sequences. Finally, by providing a more contextual basis for understanding both the rapid rates and mechanisms of enzyme-catalyzed reactions, superfamily analysis has the potential to offer insights that cannot be obtained even from the most elegant studies of a single enzyme.",
author = "Babbitt, {Patricia C.} and Gerlt, {John A.}",
year = "1997",
month = "12",
day = "5",
doi = "10.1074/jbc.272.49.30591",
language = "English (US)",
volume = "272",
pages = "30591--30594",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "49",

}

TY - JOUR

T1 - Understanding enzyme superfamilies. Chemistry as the fundamental determinant in the evolution of new catalytic activities

AU - Babbitt, Patricia C.

AU - Gerlt, John A.

PY - 1997/12/5

Y1 - 1997/12/5

N2 - We have described four superfamilies of enzymes where the members within each catalyze different overall reactions using broadly varied substrates. Within each superfamily, the different overall reactions are facilitated by a common mechanistic strategy that can be rationalized in the context of the structural scaffold. Although space limitations prevent their discussion, a number of additional superfamilies have been described in which these principles appear to obtain. Analyses of the relationships between structure and function in all of these superfamilies suggest two general conclusions regarding the evolution of new catalytic activities. 1) Nature discovered that chemistry, and not binding specificity, is the dominant factor in the evolution of new enzymatic activities. New enzymatic activities evolve by duplication of the gene for a preexisting enzyme that provides a structural strategy for a mechanistically difficult chemical step. As a result, related enzymes can differ broadly in the identity of the overall reactions they mediate as well as in substrate specificity. 2) The catalytic activity of a newly sequenced but uncharacterized open reading frame cannot necessarily be inferred from the overall reactions catalyzed by homologous enzymes. Rather, the chemical step common to the superfamily scaffold must be identified and correlated with conserved structural features. These conclusions should be useful in developing new strategies for solving problems of current interest in mechanistic enzymology and structural biology as well as in the emerging disciplines of bioinformatics. For example, determination of the principles that govern the structure-function correlations for any particular superfamily will likely play an important role in assigning catalytic function to unknown sequences. Finally, by providing a more contextual basis for understanding both the rapid rates and mechanisms of enzyme-catalyzed reactions, superfamily analysis has the potential to offer insights that cannot be obtained even from the most elegant studies of a single enzyme.

AB - We have described four superfamilies of enzymes where the members within each catalyze different overall reactions using broadly varied substrates. Within each superfamily, the different overall reactions are facilitated by a common mechanistic strategy that can be rationalized in the context of the structural scaffold. Although space limitations prevent their discussion, a number of additional superfamilies have been described in which these principles appear to obtain. Analyses of the relationships between structure and function in all of these superfamilies suggest two general conclusions regarding the evolution of new catalytic activities. 1) Nature discovered that chemistry, and not binding specificity, is the dominant factor in the evolution of new enzymatic activities. New enzymatic activities evolve by duplication of the gene for a preexisting enzyme that provides a structural strategy for a mechanistically difficult chemical step. As a result, related enzymes can differ broadly in the identity of the overall reactions they mediate as well as in substrate specificity. 2) The catalytic activity of a newly sequenced but uncharacterized open reading frame cannot necessarily be inferred from the overall reactions catalyzed by homologous enzymes. Rather, the chemical step common to the superfamily scaffold must be identified and correlated with conserved structural features. These conclusions should be useful in developing new strategies for solving problems of current interest in mechanistic enzymology and structural biology as well as in the emerging disciplines of bioinformatics. For example, determination of the principles that govern the structure-function correlations for any particular superfamily will likely play an important role in assigning catalytic function to unknown sequences. Finally, by providing a more contextual basis for understanding both the rapid rates and mechanisms of enzyme-catalyzed reactions, superfamily analysis has the potential to offer insights that cannot be obtained even from the most elegant studies of a single enzyme.

UR - http://www.scopus.com/inward/record.url?scp=0030667789&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0030667789&partnerID=8YFLogxK

U2 - 10.1074/jbc.272.49.30591

DO - 10.1074/jbc.272.49.30591

M3 - Short survey

C2 - 9388188

AN - SCOPUS:0030667789

VL - 272

SP - 30591

EP - 30594

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 49

ER -