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CTBP
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C-terminal binding proteins
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Human CtBP1 reduces a number of substrates with a relatively low activity, using NADH as a cofactor [50]. It shows the best catalytic efficiency with 2-keto-4-methylthiobutyrate, an intermediate of the methionine salvage pathway [50]. The saturation curve shows biphasic behavior, with marked substrate inhibition at elevated concentrations [50]. Physiological substrates for CTBP proteins are not known.
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Eukaryotes (vertebrates, arthropods)
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Transcriptional corepressors targeting many transcriptional regulators [51] and playing critical roles during development of both invertebrates and vertebrates [52]. They have intrinsic dehydrogenase activity and the NAD+-dependent conformational change is thought to be essential to their co-repression activity [53, 54]. Two copies (CTBP1_HUMAN, CTBP2_HUMAN) are encoded in the human genome. A. thaliana homolog (CTBP_ARATH, C-terminal binding protein AN), which is a sister clade to the CTBP family, differs substantially in sequence, lacks the catalytic residues and seems not to regulate transcription [55], therefore was excluded from the family.
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2-keto-4-methylthiobutyrate (2), 3-phosphohydroxypyruvate, 2-keto-D-gluconate, 2-ketovalerate, pyruvate, 2-ketoisocaproate, 2-ketoglutarate, phenylpyruvate, glyoxylate, 2-ketocaproate, oxaloacetate
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CTBP1_HUMAN functions equally effective with NADH and NAD+ [53, 54].
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DDH
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2-ketocarboxylic reductases with broad substrate specificity
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ddh from Haloferax mediterranei catalyzes reduction of α-ketocarboxylic acids showing marked preference for those having an unbranched chain of 4–5 carbon atoms, such as 2-ketoisoleucine [56].
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Eukaryotes (fungi, protists), archaea and bacteria (cyanobacteria, actinobacteria)
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Function unknown. Four copies encoded in the genome of a halophilic mesophile, Haloferax volcanii.
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pyruvate, 2-ketoisocaproate, 2-ketobutyrate, 2-keto-3-methylvalerate
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DDH_HALMT prefers NADPH over NADH [56].
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FDH
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formate dehydroganases
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A highly conserved group of enzymes, mostly specific to both formate and NAD+. Mechanism of the catalyzed reaction differs from that observed in other related dehydrogenases – it is specified by a direct transfer of hydride ion from the substrate onto the C4-atom of the nicotinamide moiety of NAD+ without stages of acid-base catalysis [21].
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Eukaryotes (fungi, plants) and bacteria (Firmicutes, proteobacteria)
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FDHs are involved in methanol utilization in all methylotrophic microorganisms (yeast and bacteria) [57] and in stress response in higher plants [58].
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formate (5)
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Majority FDHs are specific to NAD+ [57]. Some possess dual cofactor specificity, with NADP+ preferred over NAD+, e.g. G8NVB5_GRAMM [59] and B5A8W5_9BURK [25].
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GHRA
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glyoxylate/hydroxypyruvate reductases A
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Bacterial (mostly) group of enzymes, studied biochemically in E. coli and R. etli. They show similar substrate specificity profiles, accepting glyoxylate, hydroxypyruvate, but not pyruvate, 2-ketoglutarate and 2-keto-D-gluconate [5, 60]. In addition, R. etli GxrA reduces phenylpyruvate and 2-ketobutyrate [5].
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Bacteria (proteobacteria) and eukaryotes (arthropods, e.g., Nematostella vectensis)
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Reduction of glyoxylate [60]. E. coli YcdW could be replaced by YiaE belonging to the GHRB subfamily [60].
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hydroxypyruvate (3), glyoxylate (3), hydroxyphenylpyruvate, 2-ketobutyrate, pyruvate, phenylpyruvate
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Majority sequences have the NADPH-binding motif. GHRA_ECOLI prefers NADPH over NADH [60], Q92T34_RHIME works only with NADPH [64], while C1JH53_RHIET only with NADH [5].
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GHRB
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glyoxylate/hydroxypyruvate reductases B
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Heterogeneous and widely spread group of enzymes. They usually work most efficiently with glyoxylate and hydroxypyruvate, but not pyruvate (GRHPR_HUMAN, GHRB_ECOLI); however, some are more specific towards hydroxyphenylpyruvate (HPPR_PLESU). They group together with PTXD_PSEST, which oxidizes phosphonate, and D-mandalate dehydrogenase (Q9LLW9_RHOGR).
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Eukaryotes, bacteria and archaea
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In mammals, glyoxylate reductase, expressed primarily in kidney and liver, is involved in the serine degradation pathway [61]. GRHPR_HUMAN converts hydroxypyruvate to D-glycerate and glyoxylate to glycolate and mutations in the gene causes primary hyperoxaluria type II [4]. Hydroxyphenylpyruvate reductase in Coleus blumei (HPPR_PLESU), is involved in the rosmarinic acid biosynthesis [62], and hydroxypyruvate reductases in A. thaliana (HPR1_ARATH, HPR2_ARATH, HPR3_ARATH) in photorespiratory metabolism. In methylotrophic organisms, hydroxypyruvate reductase (DHGY_HYPME) plays a central role in carbon assimilation, converting hydroxypyruvate to glycerate as a key step in the serine cycle [63].
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hydroxypyruvate (13), glyoxylate (12), phenylpyruvate (3), pyruvate (2), 4-hydroxyphenylpyruvate (2), hydroxyphenylpyruvate, oxaloacetate, 2-keto-D-gluconate, 2-hydroxyisocaproate, D-mandalate, 2-keto-L-gulonate, phenylglyoxylate, phosphonate, 3,4-dihydroxyphenylpyruvate, benzylformate, 2-keto-D-gluconic acid
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Usually possess better affinity to NADPH than NADH (GRHPR_HUMAN [38], HPPR_PLESU [62], GHRB_ECOLI [63]), but some enzymes work better with NADH (HPR1_ARATH [68]).
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GHRC
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glyoxylate/hydroxypyruvate reductases C
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An enzyme from a methylotroph M. extorquens was shown to reduce hydroxypyruvate and glyoxylate, and catalyze reverse reaction with glycerate but not glycolate [19].
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Bacteria and archaea
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It plays a central role in assimilation of carbon in methylotrophic organisms as it converts hydroxypyruvate to glycerate as a key step in the serine cycle, may also play an important role in C2 reactions by interconverting glyoxylate and glycolate [19].
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hydroxypyruvate, glyoxylate, D-glycerate
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DHGY_METEA is active with both NADH and NADPH [19].
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LDHD
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D-lactate dehydrogenases
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According to the phylogenetic analysis, there are two subgroups within this clade: a Bacilli-specific clade and a clade comprising other bacteria and eukaryotes. Originally annotated as D-lactate dehydrogenases, work with a broad range of small substrates, but usually best with pyruvate, using NADH as a cofactor. However, 2-ketoisocaproate was shown to be the best substrate for the enzyme from L. casei [64]. E. coli LDHD was shown to be inhibited in situ by substrate in high concentrations [65]. VanH from Enterococcus faecium was shown to work best with pyruvate and 2-ketobutyrate [66], whereas relatively diverged Chlamydomonas reinhardtii D-LDH reduces pyruvate in chloroplasts and works as a tetramer [67].
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Bacteria and lower eukaryotes (protists, fungi, green alga)
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The Bacilli enzymes are postulated to reduce pyruvate, the final product of glycolysis, to lactate [68]. VanH from E. faecium is involved in vancomycin resistance [66]. Chlamydomonas reinhardtii D-LDH reduces pyruvate in fermentation pathways in chloroplasts [67].
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pyruvate (8), 2-ketobutyrate (7), phenylpyruvate (7), 2-ketovalerate (4), 2-ketoisocaproate (4), 2-ketocaproate (4), lactate (3), 2-ketoisovalerate (3), hydroxypyruvate (2), glyoxylate (2), 2-keto-3-methylbutyrate, 2-keto-4-methylmercaptobutyrate, mercaptopyruvate, 2-ketooctanoate, 2-oobutanoate, 4-hydroxyphenylpyruvate, oxaloacetate, 2-ketovalerate, 2-ketohexanoate, bromopyruvate, 2-keto-3-methylvalerate
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LDHD enzymes utilizes NADH as a cofactor [65, 67, 68].
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PDXB
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erythronate-4-phosphate dehydrogenases
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E. coli PdxB oxidizes 4-phospho-D-erythronate to 2-keto-3-hydroxy-4-phosphobutanoate [69] and uses various 2-keto acids as co-substrates [27].
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Bacteria (ɣ-proteobacteria and bacteroidetes)
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In E. coli, PdxB catalyzes the second step in the biosynthesis of pyridoxal phosphate (active form of vitamin B6) [69].
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α-ketoglutarate, 4-phospho-D-erythronate, pyruvate, oxaloacetate
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PDXB_ECOLI utilizes NADH/NAD+ as a cofactor [69].
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SERA
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3-phosphoglycerate dehydrogenases
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PGDHs can be divided into four distinct groups [70]. They convert D-3-phosphoglycerate to hydroxypyruvic acid phosphate. E. coli SerA is strongly inhibited by L-serine, the end product of the pathway, which binds to the ACT domain and allosterically regulates velocity of the catalyzed reaction [71]. Unlike Mycobacterium tuberculosis and rat SerA enzymes, E. coli SerA can also utilize α-ketoglutarate as a substrate, yet with considerably lower affinity than 3-phosphoglycerate [70].
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Eukaryotes, bacteria and archaea
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They catalyze the first committed step in the phosphorylated pathway of L-serine biosynthesis by converting D-3-phosphoglycerate to hydroxypyruvic acid phosphate [72].
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3-phosphoglycerate (6), 3-sulfopyruvate, sulfolactate, 2-ketoglutarate
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SERA enzymes utilize NAD+ as a cofactor [72].
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