The Natural History of Biocatalytic Mechanisms

Phylogenomic analysis of the occurrence and abundance of protein domains in proteomes has recently showed that the α/β architecture is probably the oldest fold design. This holds important implications for the origins of biochemistry. Here we explore structure-function relationships addressing the u...

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Published in:PLoS computational biology Vol. 10; no. 5; p. e1003642
Main Authors: Nath, Neetika, Mitchell, John B. O., Caetano-Anollés, Gustavo
Format: Journal Article
Language:English
Published: United States Public Library of Science 01.05.2014
Public Library of Science (PLoS)
Subjects:
Architecture
Biochemistry
Biology and Life Sciences
Catalysis
Chemical reactions
Classification
Enzymes
Enzymes - chemistry
Enzymes - genetics
Enzymes - ultrastructure
Evolution
Evolution, Molecular
Metabolism
Metabolites
Phylogeny
Physical Sciences
Physiological aspects
Protein Folding
Protein research
Protein Structure, Tertiary
Proteins
Structure-Activity Relationship
ISSN:1553-7358, 1553-734X, 1553-7358
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Summary:Phylogenomic analysis of the occurrence and abundance of protein domains in proteomes has recently showed that the α/β architecture is probably the oldest fold design. This holds important implications for the origins of biochemistry. Here we explore structure-function relationships addressing the use of chemical mechanisms by ancestral enzymes. We test the hypothesis that the oldest folds used the most mechanisms. We start by tracing biocatalytic mechanisms operating in metabolic enzymes along a phylogenetic timeline of the first appearance of homologous superfamilies of protein domain structures from CATH. A total of 335 enzyme reactions were retrieved from MACiE and were mapped over fold age. We define a mechanistic step type as one of the 51 mechanistic annotations given in MACiE, and each step of each of the 335 mechanisms was described using one or more of these annotations. We find that the first two folds, the P-loop containing nucleotide triphosphate hydrolase and the NAD(P)-binding Rossmann-like homologous superfamilies, were α/β architectures responsible for introducing 35% (18/51) of the known mechanistic step types. We find that these two oldest structures in the phylogenomic analysis of protein domains introduced many mechanistic step types that were later combinatorially spread in catalytic history. The most common mechanistic step types included fundamental building blocks of enzyme chemistry: "Proton transfer," "Bimolecular nucleophilic addition," "Bimolecular nucleophilic substitution," and "Unimolecular elimination by the conjugate base." They were associated with the most ancestral fold structure typical of P-loop containing nucleotide triphosphate hydrolases. Over half of the mechanistic step types were introduced in the evolutionary timeline before the appearance of structures specific to diversified organisms, during a period of architectural diversification. The other half unfolded gradually after organismal diversification and during a period that spanned ∼2 billion years of evolutionary history.
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Conceived and designed the experiments: NN JBOM GCA. Performed the experiments: NN. Analyzed the data: NN JBOM GCA. Contributed reagents/materials/analysis tools: NN JBOM GCA. Wrote the paper: NN JBOM GCA.
The authors have declared that no competing interests exist.
ISSN:1553-7358
1553-734X
1553-7358
DOI:10.1371/journal.pcbi.1003642