Pseudomonas fluorescens mannitol 2-dehydrogenase and the family of polyol-specific long-chain dehydrogenases/reductases: Sequence-based classification and analysis of structure-function relationships

Mario Klimacek, Kathryn L. Kavanagh, David K. Wilson, Bernd Nidetzky

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

Multiple sequence alignment and analysis of evolutionary relationships have been used to characterize a family of polyol-specific long-chain dehydrogenases/reductases (PSLDRs). At the present time, 66 known and putative NAD(P)H-dependent oxidoreductases of mainly prokaryotic origin and between 357 and 544 amino acids in length constitute this family. The family is shown to include D-mannitol 2-dehydrogenase, D-mannonate 5-oxidoreductase, D-altronate 5-oxidoreductase, D-arabinitol 4-dehydrogenase, and D-mannitol-1-phosphate 5-dehydrogenase which form individual sub-families (defined by internal sequence identity of ≥30%) having distant origin and divergent substrate specificity but clearly displaying entire-chain relationship. When all forms are aligned, only three residues, Gly-33, Asp-230, and Lys-295 (in the numbering of Pseudomonas fluorescens D-mannitol 2-dehydrogenase (PsM2DH)) are strictly conserved. By combining sequence alignment with the known structure of PsM2DH and results from site-directed mutagenesis, we have developed a structure/function analysis for the family. Gly-33 is in the N-terminal coenzyme-binding domain and part of a nucleotide fingerprint region for the family, and Asp-230 and Lys-295 are at an interdomain segment contributing to the active site in which the lysine likely functions as the catalytic general acid/base. PSLDRs do not require a metal cofactor for activity and are specific for transferring the 4-pro-S hydrogen from NAD(P)H. Comparisons reveal that the core part of the two-domain fold has been conserved throughout all family members, perhaps reflecting the recruitment of a stable oxidoreductase structure and extensive trimming thereof to acquire functional properties specific to each sub-family. They also identify interactions that define the chemical mechanism of oxidoreduction and likely contribute to substrate and co-substrate specificities and are thus relevant for protein engineering.

Original languageEnglish (US)
Pages (from-to)559-582
Number of pages24
JournalChemico-Biological Interactions
Volume143-144
DOIs
StatePublished - Feb 1 2003

Fingerprint

Mannitol Dehydrogenases
Pseudomonas fluorescens
Oxidoreductases
Mannitol
tagaturonate reductase
D-arabinitol dehydrogenase
Sequence Alignment
Fructuronate Reductase
mannitol-1-phosphate dehydrogenase
Substrate Specificity
Nucleotide Mapping
NAD
Substrates
Protein Engineering
polyol
Coenzymes
Mutagenesis
Trimming
Site-Directed Mutagenesis
Lysine

Keywords

  • Classification
  • Polyol-specific long-chain dehydrogenases/reductases
  • Structure/function relationships

ASJC Scopus subject areas

  • Toxicology

Cite this

Pseudomonas fluorescens mannitol 2-dehydrogenase and the family of polyol-specific long-chain dehydrogenases/reductases : Sequence-based classification and analysis of structure-function relationships. / Klimacek, Mario; Kavanagh, Kathryn L.; Wilson, David K.; Nidetzky, Bernd.

In: Chemico-Biological Interactions, Vol. 143-144, 01.02.2003, p. 559-582.

Research output: Contribution to journalArticle

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abstract = "Multiple sequence alignment and analysis of evolutionary relationships have been used to characterize a family of polyol-specific long-chain dehydrogenases/reductases (PSLDRs). At the present time, 66 known and putative NAD(P)H-dependent oxidoreductases of mainly prokaryotic origin and between 357 and 544 amino acids in length constitute this family. The family is shown to include D-mannitol 2-dehydrogenase, D-mannonate 5-oxidoreductase, D-altronate 5-oxidoreductase, D-arabinitol 4-dehydrogenase, and D-mannitol-1-phosphate 5-dehydrogenase which form individual sub-families (defined by internal sequence identity of ≥30{\%}) having distant origin and divergent substrate specificity but clearly displaying entire-chain relationship. When all forms are aligned, only three residues, Gly-33, Asp-230, and Lys-295 (in the numbering of Pseudomonas fluorescens D-mannitol 2-dehydrogenase (PsM2DH)) are strictly conserved. By combining sequence alignment with the known structure of PsM2DH and results from site-directed mutagenesis, we have developed a structure/function analysis for the family. Gly-33 is in the N-terminal coenzyme-binding domain and part of a nucleotide fingerprint region for the family, and Asp-230 and Lys-295 are at an interdomain segment contributing to the active site in which the lysine likely functions as the catalytic general acid/base. PSLDRs do not require a metal cofactor for activity and are specific for transferring the 4-pro-S hydrogen from NAD(P)H. Comparisons reveal that the core part of the two-domain fold has been conserved throughout all family members, perhaps reflecting the recruitment of a stable oxidoreductase structure and extensive trimming thereof to acquire functional properties specific to each sub-family. They also identify interactions that define the chemical mechanism of oxidoreduction and likely contribute to substrate and co-substrate specificities and are thus relevant for protein engineering.",
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N2 - Multiple sequence alignment and analysis of evolutionary relationships have been used to characterize a family of polyol-specific long-chain dehydrogenases/reductases (PSLDRs). At the present time, 66 known and putative NAD(P)H-dependent oxidoreductases of mainly prokaryotic origin and between 357 and 544 amino acids in length constitute this family. The family is shown to include D-mannitol 2-dehydrogenase, D-mannonate 5-oxidoreductase, D-altronate 5-oxidoreductase, D-arabinitol 4-dehydrogenase, and D-mannitol-1-phosphate 5-dehydrogenase which form individual sub-families (defined by internal sequence identity of ≥30%) having distant origin and divergent substrate specificity but clearly displaying entire-chain relationship. When all forms are aligned, only three residues, Gly-33, Asp-230, and Lys-295 (in the numbering of Pseudomonas fluorescens D-mannitol 2-dehydrogenase (PsM2DH)) are strictly conserved. By combining sequence alignment with the known structure of PsM2DH and results from site-directed mutagenesis, we have developed a structure/function analysis for the family. Gly-33 is in the N-terminal coenzyme-binding domain and part of a nucleotide fingerprint region for the family, and Asp-230 and Lys-295 are at an interdomain segment contributing to the active site in which the lysine likely functions as the catalytic general acid/base. PSLDRs do not require a metal cofactor for activity and are specific for transferring the 4-pro-S hydrogen from NAD(P)H. Comparisons reveal that the core part of the two-domain fold has been conserved throughout all family members, perhaps reflecting the recruitment of a stable oxidoreductase structure and extensive trimming thereof to acquire functional properties specific to each sub-family. They also identify interactions that define the chemical mechanism of oxidoreduction and likely contribute to substrate and co-substrate specificities and are thus relevant for protein engineering.

AB - Multiple sequence alignment and analysis of evolutionary relationships have been used to characterize a family of polyol-specific long-chain dehydrogenases/reductases (PSLDRs). At the present time, 66 known and putative NAD(P)H-dependent oxidoreductases of mainly prokaryotic origin and between 357 and 544 amino acids in length constitute this family. The family is shown to include D-mannitol 2-dehydrogenase, D-mannonate 5-oxidoreductase, D-altronate 5-oxidoreductase, D-arabinitol 4-dehydrogenase, and D-mannitol-1-phosphate 5-dehydrogenase which form individual sub-families (defined by internal sequence identity of ≥30%) having distant origin and divergent substrate specificity but clearly displaying entire-chain relationship. When all forms are aligned, only three residues, Gly-33, Asp-230, and Lys-295 (in the numbering of Pseudomonas fluorescens D-mannitol 2-dehydrogenase (PsM2DH)) are strictly conserved. By combining sequence alignment with the known structure of PsM2DH and results from site-directed mutagenesis, we have developed a structure/function analysis for the family. Gly-33 is in the N-terminal coenzyme-binding domain and part of a nucleotide fingerprint region for the family, and Asp-230 and Lys-295 are at an interdomain segment contributing to the active site in which the lysine likely functions as the catalytic general acid/base. PSLDRs do not require a metal cofactor for activity and are specific for transferring the 4-pro-S hydrogen from NAD(P)H. Comparisons reveal that the core part of the two-domain fold has been conserved throughout all family members, perhaps reflecting the recruitment of a stable oxidoreductase structure and extensive trimming thereof to acquire functional properties specific to each sub-family. They also identify interactions that define the chemical mechanism of oxidoreduction and likely contribute to substrate and co-substrate specificities and are thus relevant for protein engineering.

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