Classification, substrate specificity and structural features of D-2-hydroxyacid dehydrogenases: 2HADH knowledgebase

Matelska, Dorota; Shabalin, I.G.; Jabłońska, Jagoda; Domagalski, Marcin J.; Kutner, Jan; Ginalski, Krzysztof; Minor, W.

doi:10.1186/s12862-018-1309-8

Cited by 22 publications

(26 citation statements)

References 113 publications

(240 reference statements)

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“…Our phylogenetic analysis (Fig. S4 ) indicates that the enzyme is a bona fide NAD + -dependent Fdh within the superfamily of D-2-hydroxyacid dehydrogenases [ 76 ]. This indicates the capacity to use formate for supplementing CO 2 needs while concomitantly supplying reducing equivalents (as in methylotrophs [ 77 , 78 ]).…”

Section: Resultsmentioning

confidence: 99%

Genomes of Thaumarchaeota from deep sea sediments reveal specific adaptations of three independently evolved lineages

et al. 2021

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Marine sediments represent a vast habitat for complex microbiomes. Among these, ammonia oxidizing archaea (AOA) of the phylum Thaumarchaeota are one of the most common, yet little explored, inhabitants, which seem extraordinarily well adapted to the harsh conditions of the subsurface biosphere. We present 11 metagenome-assembled genomes of the most abundant AOA clades from sediment cores obtained from the Atlantic Mid-Ocean ridge flanks and Pacific abyssal plains. Their phylogenomic placement reveals three independently evolved clades within the order Nitrosopumilales, of which no cultured representative is known yet. In addition to the gene sets for ammonia oxidation and carbon fixation known from other AOA, all genomes encode an extended capacity for the conversion of fermentation products that can be channeled into the central carbon metabolism, as well as uptake of amino acids probably for protein maintenance or as an ammonia source. Two lineages encode an additional (V-type) ATPase and a large repertoire of DNA repair systems that may allow to overcome the challenges of high hydrostatic pressure. We suggest that the adaptive radiation of AOA into marine sediments occurred more than once in evolution and resulted in three distinct lineages with particular adaptations to this extremely energy-limiting and high-pressure environment.

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Section: Resultsmentioning

confidence: 99%

Genomes of Thaumarchaeota from deep sea sediments reveal specific adaptations of three independently evolved lineages

et al. 2021

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“…In addition, these five residues are also structurally conserved and fully buried in the interface among the SerA subfamily via structure-based sequence alignment with known PGDH structures (PDB codes: 2G76 , 4NJO , 1YBA , 1YGY , 3K5P , 1WWK , and 2EKL ) ( Fig. S2 ) ( 20 , 23 , 39 , 40 ). Protein–protein interaction studies have suggested that hot spots are likely to be structurally conserved residues and are organized in high packing density regions.…”

Section: Resultsmentioning

confidence: 99%

“…PHGDH belongs to the SerA subset of D-isomer-specific 2-hydroxyacid-dehydrogenase (2HADH) family that catalyzes the stereospecific reductions of 2-keto acids to corresponding 2-hydroxy acids ( 20 ). D-3-phosphoglycerate dehydrogenases (PGDHs) expressed in various organisms are grouped into three types based on their domain arrangement.…”

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confidence: 99%

Dimerization of PHGDH via the catalytic unit is essential for its enzymatic function

Qing

Wang

et al. 2021

Journal of Biological Chemistry

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Human D-3-phosphoglycerate dehydrogenase (PHGDH), a key enzyme in de novo serine biosynthesis, is amplified in various cancers and serves as a potential target for anticancer drug development. To facilitate this process, more information is needed on the basic biochemistry of this enzyme. For example, PHGDH was found to form tetramers in solution and the structure of its catalytic unit (sPHGDH) was solved as a dimer. However, how the oligomeric states affect PHGDH enzyme activity remains elusive. We studied the dependence of PHGDH enzymatic activity on its oligomeric states. We found that sPHGDH forms a mixture of monomers and dimers in solution with a dimer dissociation constant of ∼0.58 μM, with the enzyme activity depending on the dimer content. We computationally identified hotspot residues at the sPHGDH dimer interface. Single-point mutants at these sites disrupt dimer formation and abolish enzyme activity. Molecular dynamics simulations showed that dimer formation facilitates substrate binding and maintains the correct conformation required for enzyme catalysis. We further showed that the full-length PHGDH exists as a dynamic mixture of monomers, dimers, and tetramers in solution with enzyme concentration-dependent activity. Mutations that can completely disrupt the sPHGDH dimer show different abilities to interrupt the full-length PHGDH tetramer. Among them, E108A and I121A can also disrupt the oligomeric structures of the full-length PHGDH and abolish its enzyme activity. Our study indicates that disrupting the oligomeric structure of PHGDH serves as a novel strategy for PHGDH drug design and the hotspot residues identified can guide the design process.

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“…The ribose of the adenosine moiety is bound by two hydrogen bonds with the conserved, negatively charged side chain of D45, suggesting the enzyme has a strong preference for NAD + . Binding of the 2′‐phosphate of NADP + is likely prevented due to the steric interference and the negative charge of D45, as is observed in many TyrA proteins and other NAD + /NADP + ‐dependent dehydrogenases . Altogether, the overall fold of BaPDH's catalytic core is highly similar to other bacterial PDHs as represented by AaPDH (Fig.…”

Section: Resultsmentioning

confidence: 79%

Structural and biochemical analysis of Bacillus anthracis prephenate dehydrogenase reveals an unusual mode of inhibition by tyrosine via the ACT domain

et al. 2019

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Tyrosine biosynthesis via the shikimate pathway is absent in humans and other animals, making it an attractive target for next‐generation antibiotics, which is increasingly important due to the looming proliferation of multidrug‐resistant pathogens. Tyrosine biosynthesis is also of commercial importance for the environmentally friendly production of numerous compounds, such as pharmaceuticals, opioids, aromatic polymers, and petrochemical aromatics. Prephenate dehydrogenase (PDH) catalyzes the penultimate step of tyrosine biosynthesis in bacteria: the oxidative decarboxylation of prephenate to 4‐hydroxyphenylpyruvate. The majority of PDHs are competitively inhibited by tyrosine and consist of a nucleotide‐binding domain and a dimerization domain. Certain PDHs, including several from pathogens on the World Health Organization priority list of antibiotic‐resistant bacteria, possess an additional ACT domain. However, biochemical and structural knowledge was lacking for these enzymes. In this study, we successfully established a recombinant protein expression system for PDH from Bacillus anthracis (BaPDH), the causative agent of anthrax, and determined the structure of a BaPDH ternary complex with NAD+ and tyrosine, a binary complex with tyrosine, and a structure of an isolated ACT domain dimer. We also conducted detailed kinetic and biophysical analyses of the enzyme. We show that BaPDH is allosterically regulated by tyrosine binding to the ACT domains, resulting in an asymmetric conformation of the BaDPH dimer that sterically prevents prephenate binding to either active site. The presented mode of allosteric inhibition is unique compared to both the competitive inhibition established for other PDHs and to the allosteric mechanisms for other ACT‐containing enzymes. This study provides new structural and mechanistic insights that advance our understanding of tyrosine biosynthesis in bacteria. Enzymes Prephenate dehydrogenase from Bacillus anthracis (PDH): EC database ID: https://www.brenda-enzymes.org/enzyme.php?ecno=1.3.1.12. Databases Coordinates and structure factors have been deposited in the Protein Data Bank (PDB) with accession numbers PDB ID: http://www.rcsb.org/pdb/search/structidSearch.do?structureId=6U60 (BaPDH complex with NAD+ and tyrosine), PDB ID: http://www.rcsb.org/pdb/search/structidSearch.do?structureId=5UYY (BaPDH complex with tyrosine), and PDB ID: http://www.rcsb.org/pdb/search/structidSearch.do?structureId=5V0S (BaPDH isolated ACT domain dimer). The diffraction images are available at http://proteindiffraction.org with DOIs: https://doi.org/10.18430/M35USC, https://doi.org/10.18430/M35UYY, and https://doi.org/10.18430/M35V0S.

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Classification, substrate specificity and structural features of D-2-hydroxyacid dehydrogenases: 2HADH knowledgebase

Cited by 22 publications

References 113 publications

Genomes of Thaumarchaeota from deep sea sediments reveal specific adaptations of three independently evolved lineages

Genomes of Thaumarchaeota from deep sea sediments reveal specific adaptations of three independently evolved lineages

Dimerization of PHGDH via the catalytic unit is essential for its enzymatic function

Structural and biochemical analysis of Bacillus anthracis prephenate dehydrogenase reveals an unusual mode of inhibition by tyrosine via the ACT domain

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