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New biochemistry in the Rhodanese-phosphatase superfamily: emerging roles in diverse metabolic processes, nucleic acid modifications, and biological conflicts.

ABSTRACT: The protein-tyrosine/dual-specificity phosphatases and rhodanese domains constitute a sprawling superfamily of Rossmannoid domains that use a conserved active site with a cysteine to catalyze a range of phosphate-transfer, thiotransfer, selenotransfer and redox activities. While these enzymes have been extensively studied in the context of protein/lipid head group dephosphorylation and various thiotransfer reactions, their overall diversity and catalytic potential remain poorly understood. Using comparative genomics and sequence/structure analysis, we comprehensively investigate and develop a natural classification for this superfamily. As a result, we identified several novel clades, both those which retain the catalytic cysteine and those where a distinct active site has emerged in the same location (e.g. diphthine synthase-like methylases and RNA 2' OH ribosyl phosphate transferases). We also present evidence that the superfamily has a wider range of catalytic capabilities than previously known, including a set of parallel activities operating on various sugar/sugar alcohol groups in the context of NAD+-derivatives and RNA termini, and potential phosphate transfer activities involving sugars and nucleotides. We show that such activities are particularly expanded in the RapZ-C-DUF488-DUF4326 clade, defined here for the first time. Some enzymes from this clade are predicted to catalyze novel DNA-end processing activities as part of nucleic-acid-modifying systems that are likely to function in biological conflicts between viruses and their hosts.

SUBMITTER: Burroughs AM

PROVIDER: S-EPMC10034599 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature

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New biochemistry in the Rhodanese-phosphatase superfamily: emerging roles in diverse metabolic processes, nucleic acid modifications, and biological conflicts.

Burroughs A Maxwell AM Aravind L L

NAR genomics and bioinformatics 20230323 1

The protein-tyrosine/dual-specificity phosphatases and rhodanese domains constitute a sprawling superfamily of Rossmannoid domains that use a conserved active site with a cysteine to catalyze a range of phosphate-transfer, thiotransfer, selenotransfer and redox activities. While these enzymes have been extensively studied in the context of protein/lipid head group dephosphorylation and various thiotransfer reactions, their overall diversity and catalytic potential remain poorly understood. Using ...[more]

PMID: 36968430

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Project description:In recent years, it has become increasingly clear that promiscuity plays a key role in the evolution of new enzyme function. This finding has helped to elucidate fundamental aspects of molecular evolution. While there has been extensive experimental work on enzyme promiscuity, computational modeling of the chemical details of such promiscuity has traditionally fallen behind the advances in experimental studies, not least due to the nearly prohibitive computational cost involved in examining multiple substrates with multiple potential mechanisms and binding modes in atomic detail with a reasonable degree of accuracy. However, recent advances in both computational methodologies and power have allowed us to reach a stage in the field where we can start to overcome this problem, and molecular simulations can now provide accurate and efficient descriptions of complex biological systems with substantially less computational cost. This has led to significant advances in our understanding of enzyme function and evolution in a broader sense. Here, we will discuss currently available computational approaches that can allow us to probe the underlying molecular basis for enzyme specificity and selectivity, discussing the inherent strengths and weaknesses of each approach. As a case study, we will discuss recent computational work on different members of the alkaline phosphatase superfamily (AP) using a range of different approaches, showing the complementary insights they have provided. We have selected this particular superfamily, as it poses a number of significant challenges for theory, ranging from the complexity of the actual reaction mechanisms involved to the reliable modeling of the catalytic metal centers, as well as the very large system sizes. We will demonstrate that, through current advances in methodologies, computational tools can provide significant insight into the molecular basis for catalytic promiscuity, and, therefore, in turn, the mechanisms of protein functional evolution.

Dataset Information

New biochemistry in the Rhodanese-phosphatase superfamily: emerging roles in diverse metabolic processes, nucleic acid modifications, and biological conflicts.

Publications

New biochemistry in the Rhodanese-phosphatase superfamily: emerging roles in diverse metabolic processes, nucleic acid modifications, and biological conflicts.

Similar Datasets

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