Origins of Specificity and Promiscuity in Metabolic Networks

Carbonell, Pablo; Lecointre, Guillaume; Faulon, Jean‐Loup

doi:10.1074/jbc.m111.274050

Cited by 78 publications

(81 citation statements)

References 46 publications

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“…35 The presence of this broad substrate specificity and easy adaptability in these families of hydrolases matches with the observed higher promiscuity present in lipid metabolizing enzymes and in enzymes from actinobacteria. 36 Members of the ybfF hydrolase family have also drawn interest due to their biocatalytic potential. 16−18 For example, the ybfF hydrolase from E. coli utilizes its bifurcated binding pocket to efficiently catalyze a rapid, stereoselective reaction with 1,2-O-isopropyideneglycerol (IPG) esters, a potential pharmaceutical starting material in the production of β-blockers, prostaglandins, and leukotrienes.…”

Section: ■ Discussionmentioning

confidence: 99%

Distinct Substrate Selectivity of a Metabolic Hydrolase from Mycobacterium tuberculosis

et al. 2014

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The transition between dormant and active Mycobacterium tuberculosis infection requires reorganization of its lipid metabolism and activation of a battery of serine hydrolase enzymes. Among these serine hydrolases, Rv0045c is a mycobacterial-specific serine hydrolase with limited sequence homology outside mycobacteria but structural homology to divergent bacterial hydrolase families. Herein, we determined the global substrate specificity of Rv0045c against a library of fluorogenic hydrolase substrates, constructed a combined experimental and computational model for its binding pocket, and performed comprehensive substitutional analysis to develop a structural map of its binding pocket. Rv0045c showed strong substrate selectivity toward short, straight chain alkyl esters with the highest activity toward four atom chains. This strong substrate preference was maintained through the combined action of residues in a flexible loop connecting the cap and α/β hydrolase domains and in residues close to the catalytic triad. Two residues bracketing the substrate-binding pocket (Gly90 and His187) were essential to maintaining the narrow substrate selectivity of Rv0045c toward various acyl ester substituents, as independent conversion of these residues significantly increased its catalytic activity and broadened its substrate specificity. Focused saturation mutagenesis of position 187 implicated this residue, as the differentiation point between the substrate specificity of Rv0045c and the structurally homologous ybfF hydrolase family. Insertion of the analogous tyrosine residue from ybfF hydrolases into Rv0045c increased the catalytic activity of Rv0045 by over 20-fold toward diverse ester substrates. The unique binding pocket structure and selectivity of Rv0045c provide molecular indications of its biological role and evidence for expanded substrate diversity in serine hydrolases from M. tuberculosis.

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Section: ■ Discussionmentioning

confidence: 99%

Distinct Substrate Selectivity of a Metabolic Hydrolase from Mycobacterium tuberculosis

et al. 2014

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“…As much as the KEGG database is conceptually analogous to the EC categorization of function, this method focuses on catalytic promiscuity. The approach has been used to understand design and evolution of metabolic networks and provides a metric to examine the distribution of promiscuity or specificity across species or temporally through evolution [61]. For example, the method predicts that enzymes involved in amino acid and lipid metabolism are among the most promiscuous and therefore are among the oldest enzymes, which supported the types of reactions required for the broadest range of life forms.…”

Section: Methods For Measuring Promiscuitymentioning

confidence: 99%

Biological messiness vs. biological genius: Mechanistic aspects and roles of protein promiscuity

Atkins

2015

The Journal of Steroid Biochemistry and Molecular Biology

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In contrast to the traditional biological paradigms focused on ‘specificity’, recent research and theoretical efforts have focused on functional ‘promiscuity’ exhibited by proteins and enzymes in many biological settings, including enzymatic detoxication, steroid biochemistry, signal transduction and immune responses. In addition, divergent evolutionary processes are apparently facilitated by random mutations that yield promiscuous enzyme intermediates. The intermediates, in turn, provide opportunities for further evolution to optimize new functions from existing protein scaffolds. In some cases, promiscuity may simply represent the inherent plasticity of proteins resulting from their polymeric nature with distributed conformational ensembles. Enzymes or proteins that bind or metabolize noncognate substrates create ‘messiness’ or noise in the systems they contribute to. With our increasing awareness of the frequency of these promiscuous behaviors it becomes interesting and important to understand the molecular bases for promiscuous behavior and to distinguish between evolutionarily selected promiscuity and evolutionarily tolerated messiness. This review provides an overview of current understanding of these aspects of protein biochemistry and enzymology.

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“…Substrate promiscuity has been described as the ability of enzymes to perform comparable chemical transformations using different substrates, which allow microbes to degrade different compounds [4,12]. In this regard, the capability of an enzyme to process more than one substrate is intimately related to its evolvability, and promiscuous enzymes are more likely to appear uniformly distributed across species in the tree of life [13]. In contrast, catalytic promiscuous enzymes carry out a secondary reaction that results in a chemical transformation different from that catalyzed with its canonical substrate [11].…”

Section: How Many Kinds Of Promiscuity Are There?mentioning

confidence: 99%

“…2). The highest number of promiscuous enzymes identified in free-living organisms may be the consequence of an adaptation mechanism to survive in fluctuating ecological environments, such as in the Deinococcus-Thermus phylum which are highly resistant to environmental hazards [13]. The presence of a large proportion of promiscuous enzymes would allow the establishment of internal metabolic fluxes that can vary depending on environmental conditions, coupled with lower regulating promiscuous enzymes which enable rapid reprogramming of metabolic response, i.e., promiscuous enzymes would be subjected to less metabolic regulation than specialist enzymes, as it was previously suggested in E. coli [2].…”

Section: The Content Of Microbial Promiscuous Enzymes Is Influenced Bmentioning

confidence: 99%

Do lifestyles influence the presence of promiscuous enzymes in bacteria and Archaea metabolism?

Martínez-Núñez

Pérez‐Rueda

2016

Sustain Chem Process

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The adequacy of an organism to the environment depends in part on its ability to modify its repertoire of cellular components, such as transporters, regulatory proteins and metabolic enzymes. In this review we discuss some recent results showing how the environment influences the content of promiscuous enzymes in bacterial and archaeal metabolism. In this regard, the proportion of promiscuous enzymes do not depend on genome size, as has been reported for the complete repertoire of enzymes, but it is influenced by the lifestyles, where the fraction of promiscuous enzymes is high in free-living organisms, while there is a small fraction in intracellular organisms. Therefore, promiscuous enzymes are enriched in organisms that inhabit fluctuating environments, providing bacteria with an enzymatic repertoire of new activities that helps to face multiple ecological variables. Finally, we discuss the possible role of gene duplications that occur most frequently in promiscuous enzymes of free-living organisms, which aid expand the universe of possible functions.

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Origins of Specificity and Promiscuity in Metabolic Networks

Cited by 78 publications

References 46 publications

Distinct Substrate Selectivity of a Metabolic Hydrolase from Mycobacterium tuberculosis

Distinct Substrate Selectivity of a Metabolic Hydrolase from Mycobacterium tuberculosis

Biological messiness vs. biological genius: Mechanistic aspects and roles of protein promiscuity

Do lifestyles influence the presence of promiscuous enzymes in bacteria and Archaea metabolism?

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