Crystal Structures of Δ1-Piperideine-2-carboxylate/Δ1-Pyrroline-2-carboxylate Reductase Belonging to a New Family of NAD(P)H-dependent Oxidoreductases

Goto, Masaru; Muramatsu, Hisashi; Mihara, Hisaaki; Kurihara, Tatsuo; Esaki, Nobuyoshi; Omi, R.; Miyahara, Ikuko; Hirotsu, Ken

doi:10.1074/jbc.m507399200

Cited by 40 publications

(43 citation statements)

References 44 publications

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“…In summary, pyrrole-2-carboxylate is an effective inhibitor of ketimine reductase/CRYM mainly as a result of the NH hydrogen bonding to an active site residue; on the other hand, picolinate is a much poorer inhibitor because it does not possess a ring -NH and relies on a relatively weak ring interaction. It should be noted that the results of our inhibitor studies with ketimine reductase/ CRYM are similar to those found previously for the bacterial orthologue of ketimine reductase/CRYM, namely Pseudomonas syringae P2C reductase, where pyrrole-2-carboxylate was found to be a much better inhibitor than is picolinate [47].…”

Section: Enzyme Inhibitionsupporting

confidence: 88%

“…5) and in the mouse ketimine reductase/CRYM (PDB: 4BV9), when pyruvate is bound, it forms part of an H-bond network [36]. In contrast, the bacterial non-homologous P2C/Pyr2C reductase uses a His/Ser/Asp catalytic triad [47]. The conserved Ser90/His91 residues in mouse ketimine reductase/CRYM cannot function as part of a catalytic triad.…”

Section: In Silico Docking Of Substrates and Inhibitorsmentioning

confidence: 99%

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Insights into Enzyme Catalysis and Thyroid Hormone Regulation of Cerebral Ketimine Reductase/μ-Crystallin Under Physiological Conditions

et al. 2015

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Mammalian ketimine reductase is identical to μ-crystallin (CRYM)-a protein that is also an important thyroid hormone binding protein. This dual functionality implies a role for thyroid hormones in ketimine reductase regulation and also a reciprocal role for enzyme catalysis in thyroid hormone bioavailability. In this research we demonstrate potent sub-nanomolar inhibition of enzyme catalysis at neutral pH by the thyroid hormones L-thyroxine and 3,5,3'-triiodothyronine, whereas other thyroid hormone analogues were shown to be far weaker inhibitors. We also investigated (a) enzyme inhibition by the substrate analogues pyrrole-2-carboxylate, 4,5-dibromopyrrole-2-carboxylate and picolinate, and (b) enzyme catalysis at neutral pH of the cyclic ketimines S-(2-aminoethyl)-L-cysteine ketimine (owing to the complex nomenclature trivial names are used for the sulfur-containing cyclic ketimines as per the original authors' descriptions) (AECK), Δ(1)-piperideine-2-carboxylate (P2C), Δ(1)-pyrroline-2-carboxylate (Pyr2C) and Δ(2)-thiazoline-2-carboxylate. Kinetic data obtained at neutral pH suggests that ketimine reductase/CRYM plays a major role as a P2C/Pyr2C reductase and that AECK is not a major substrate at this pH. Thus, ketimine reductase is a key enzyme in the pipecolate pathway, which is the main lysine degradation pathway in the brain. In silico docking of various ligands into the active site of the X-ray structure of the enzyme suggests an unusual catalytic mechanism involving an arginine residue as a proton donor. Given the critical importance of thyroid hormones in brain function this research further expands on our knowledge of the connection between amino acid metabolism and regulation of thyroid hormone levels.

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Section: Enzyme Inhibitionsupporting

confidence: 88%

Section: In Silico Docking Of Substrates and Inhibitorsmentioning

confidence: 99%

Insights into Enzyme Catalysis and Thyroid Hormone Regulation of Cerebral Ketimine Reductase/μ-Crystallin Under Physiological Conditions

et al. 2015

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“… A , The amino acid sequences of AllD are compared with members of the NAD(P)H-dependent oxidoreductase family with known structures: TMLDH annotated as Thermus thermophilus HB8 Type 2 malate/lactate dehydrogenase (1VBI; Z-score, 45.3; rmsd , 1.5 Å), AMDH annotated as Agrobacterium tumefaciens malate dehydrogenase (1Z2I; Z-score, 44.3; rmsd , 1.5 Å), SLDH for Methanocaldococcus l -sulfolactate dehydrogenase (2X06; Z-score, 41.6; rmsd , 1.9 Å) [23], PMDH annotated as Pyrococcus horikoshii OT3 malate dehydrogenase (1V9N; Z-score, 41.1; rmsd , 1.6 Å), EMDH annotated as Entamoeba histolytica malate dehydrogenase (3I0P; Z-score, 40.6; rmsd , 2.1 Å), DpkA for Pseudomonas syringae Δ 1 -piperideine-2-carboxylate/Δ 1 -pyrroline-2-carboxylate reductase (2CWF; Z-score, 37.4; rmsd , 2.2 Å) [24], EMLDH annotated as E. coli malate/ l -lactate dehydrogenases (2G8Y; Z-score, 37.0; rmsd , 2.4 Å), YiaK for E. coli 2,3-diketo- l -gulonate reductase (1S20; Z-score, 36.1; rmsd , 2.7 Å) [25]. Highly conserved residues are shown in red and boxed in blue; strictly conserved residues are shown on a red background.…”

Section: Resultsmentioning

confidence: 99%

Structural and Functional Insights into (S)-Ureidoglycolate Dehydrogenase, a Metabolic Branch Point Enzyme in Nitrogen Utilization

et al. 2012

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Nitrogen metabolism is one of essential processes in living organisms. The catabolic pathways of nitrogenous compounds play a pivotal role in the storage and recovery of nitrogen. In Escherichia coli, two different, interconnecting metabolic routes drive nitrogen utilization through purine degradation metabolites. The enzyme (S)-ureidoglycolate dehydrogenase (AllD), which is a member of l-sulfolactate dehydrogenase-like family, converts (S)-ureidoglycolate, a key intermediate in the purine degradation pathway, to oxalurate in an NAD(P)-dependent manner. Therefore, AllD is a metabolic branch-point enzyme for nitrogen metabolism in E. coli. Here, we report crystal structures of AllD in its apo form, in a binary complex with NADH cofactor, and in a ternary complex with NADH and glyoxylate, a possible spontaneous degradation product of oxalurate. Structural analyses revealed that NADH in an extended conformation is bound to an NADH-binding fold with three distinct domains that differ from those of the canonical NADH-binding fold. We also characterized ligand-induced structural changes, as well as the binding mode of glyoxylate, in the active site near the NADH nicotinamide ring. Based on structural and kinetic analyses, we concluded that AllD selectively utilizes NAD+ as a cofactor, and further propose that His116 acts as a general catalytic base and that a hydride transfer is possible on the B-face of the nicotinamide ring of the cofactor. Other residues conserved in the active sites of this novel l-sulfolactate dehydrogenase-like family also play essential roles in catalysis.

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“…This is similar to the recently modified catalytic mechanism of human HAD, 12 but differs from that of the catalytic His-Asp dyad for glucose 6-phosphate dehydrogenases 23 and malate/lactate dehydrogenases, 24 and from that of the catalytic His-Ser-Asp triad for enzymes in the new NAD(P)-dependent oxidoreductases family. 25 It was reported that a mutation at Asn196 of the rabbit GDH into Asp or Gln also produces almost inactive enzymes. 5 In the current crystal structure, Asn196 is far (N 5 Å) away from His145, and its side chain N δ2 is hydrogen bonded to the C-5 and C-6 hydroxyls of the modeled L-gulonate (Fig.…”

Section: Reaction Mechanism Of Gdh Involving a Network-based Substratmentioning

confidence: 99%

Dimeric Crystal Structure of Rabbit l-Gulonate 3-Dehydrogenase/λ-Crystallin: Insights into the Catalytic Mechanism

Asada

Kuroishi

Ukita

et al. 2010

Journal of Molecular Biology

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Crystal Structures of Δ1-Piperideine-2-carboxylate/Δ1-Pyrroline-2-carboxylate Reductase Belonging to a New Family of NAD(P)H-dependent Oxidoreductases

Cited by 40 publications

References 44 publications

Insights into Enzyme Catalysis and Thyroid Hormone Regulation of Cerebral Ketimine Reductase/μ-Crystallin Under Physiological Conditions

Insights into Enzyme Catalysis and Thyroid Hormone Regulation of Cerebral Ketimine Reductase/μ-Crystallin Under Physiological Conditions

Structural and Functional Insights into (S)-Ureidoglycolate Dehydrogenase, a Metabolic Branch Point Enzyme in Nitrogen Utilization

Dimeric Crystal Structure of Rabbit l-Gulonate 3-Dehydrogenase/λ-Crystallin: Insights into the Catalytic Mechanism

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