Structural Basis for a Cofactor-dependent Oxidation Protection and Catalysis of Cyanobacterial Succinic Semialdehyde Dehydrogenase

Park, Jinseo; Rhee, Sangkee

doi:10.1074/jbc.m113.460428

Cited by 17 publications

(61 citation statements)

References 36 publications

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“…However, all these instances are adducts between the pyridine and a Cys residue from the protein (Fig. C–E) . To the best of our knowledge, this is the first structural evidence of a protein mediated NADP–low‐molecular‐mass thiol adduct bound to a protein active site.…”

Section: Resultsmentioning

confidence: 77%

“…Under alkaline conditions, NADP + is known to participate in nucleophilic addition reactions with sulfhydryl compounds like sulfides, cysteines and a range of mercaptans, including dithiols to form 1,2-or 1,4-adducts with the nicotinamide moiety [43]. Structural evidence for the NADP-Cys adduct has been reported earlier in Synechococcus succinic semialdehyde dehydrogenase (SySSADH), Rattus 10-formyltetrahydrofolate dehydrogenase (RaFDH), and Pseudomonas aeruginosa betaine aldehyde dehydrogenase [40][41][42]. Although these complexes may result from 'charge-transfer' reactions, the ability to purify the adducts suggests an actual addition reaction [40][41][42]55].…”

Section: Formation Of Nadp-dtt Adductmentioning

confidence: 99%

“…9B). Although NADPH and reduced DTT were initially present in the crystallization cocktail, it is likely that coupled auto-oxidation has occurred under the alkaline pH (HEPES pH 7.5) and aerobic nature of the crystallization conditions, thus favoring the reaction [42,56,57]. We also propose a structural argument where competitive inhibition by DTT, a thiol analog of the reaction product, helps retain an appropriate orientation that favors the interaction of the C4N atom of the nicotinamide ring and the thiolate.…”

Section: Formation Of Nadp-dtt Adductmentioning

confidence: 99%

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Crystal structure of yeast xylose reductase in complex with a novel NADP‐DTT adduct provides insights into substrate recognition and catalysis

2018

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Aldose reductases (ARs) belonging to the aldo‐keto reductase (AKR) superfamily catalyze the conversion of carbonyl substrates into their respective alcohols. Here we report the crystal structures of the yeast Debaryomyces nepalensis xylose reductase (DnXR, AKR2B10) in the apo form and as a ternary complex with a novel NADP‐DTT adduct. Xylose reductase, a key enzyme in the conversion of xylose to xylitol, has several industrial applications. The enzyme displayed the highest catalytic efficiency for l‐threose (138 ± 7 mm−1·s−1) followed by d‐erythrose (30 ± 3 mm−1·s−1). The crystal structure of the complex reveals a covalent linkage between the C4N atom of the nicotinamide ring of the cosubstrate and the S1 sulfur atom of DTT and provides the first structural evidence for a protein mediated NADP–low‐molecular‐mass thiol adduct. We hypothesize that the formation of the adduct is facilitated by an in‐crystallo Michael addition of the DTT thiolate to the specific conformation of bound NADPH in the active site of DnXR. The interactions between DTT, a four‐carbon sugar alcohol analog, and the enzyme are representative of a near‐cognate product ternary complex and provide significant insights into the structural basis of aldose binding and specificity and the catalytic mechanism of ARs. Database Structural data are available in the PDB under the accession numbers http://www.rcsb.org/pdb/search/structidSearch.do?structureId=5ZCI and http://www.rcsb.org/pdb/search/structidSearch.do?structureId=5ZCM.

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Section: Resultsmentioning

confidence: 77%

Section: Formation Of Nadp-dtt Adductmentioning

confidence: 99%

Section: Formation Of Nadp-dtt Adductmentioning

confidence: 99%

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Crystal structure of yeast xylose reductase in complex with a novel NADP‐DTT adduct provides insights into substrate recognition and catalysis

2018

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“…Such an active-site asparagine residue is hypothesized to provide catalytic contribution as an oxyanion hole residue in other aldehyde dehydrogenases (10,11). Substitution of the asparagine by alanine eliminated the dehydrogenase activity (12,13). However, the precise role of the asparagine residue remains unexplored in any member of the aldehyde dehydrogenase superfamily, including AMSDH.…”

mentioning

confidence: 99%

A Pitcher-and-Catcher Mechanism Drives Endogenous Substrate Isomerization by a Dehydrogenase in Kynurenine Metabolism

Yang

Davis

et al. 2016

Journal of Biological Chemistry

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Edited by Ruma BanerjeeAldehyde dehydrogenase typically performs oxidation of aldehydes to their corresponding carboxylic acid while reducing NAD(P)؉ to NAD(P)H via covalent catalysis mediated by an active-site cysteine residue. These data establish a hidden intrinsic isomerization activity of the dehydrogenase and allow us to propose a pitcher-catcher type of catalytic mechanism for the isomerization.The kynurenine pathway is the catabolic route for tryptophan degradation in mammals and certain bacteria. In mammals, the pathway has been found to produce neuroactive compounds that correlate with depression and neurodegenerative disease states such as Alzheimer's, Parkinson's, and Huntington's diseases (1-3). Moreover, the kynurenine pathway is a de novo biosynthetic route to produce the coenzyme NAD ϩ / NADH, which is involved in many fundamental biological processes as an energy carrier and redox mediator. In the kynurenine pathway, tryptophan metabolites are partitioned by both enzymatic and non-enzymatic reactions (4). Three consecutive enzymes of the pathway, 3-hydroxyanthranilate dioxygenase (HAO), 3 2-amino-3-carboxymuconate-6-semi-aldehyde decarboxylase (ACMSD), and 2-amino-muconate-6-semialdehyde dehydrogenase (AMSDH), compete with the non-enzymatic auto-cyclization of their substrates and products for further metabolism (Fig. 1). The trio of enzymes is also present in the 2-nitrobenzoic acid biodegradation pathway.Investigations at the molecular level of the kynurenine pathway were extended to AMSDH in our recent work (5). AMSDH is a 216-kDa homotetrameric protein (500 amino acid residues in each subunit) that belongs to the aldehyde dehydrogenase superfamily. It competes with a spontaneous, non-enzymatic cyclization of 2-aminomuconate semialdehyde (2-AMS) to prevent overproduction of picolinic acid. The off-pathway product, picolinic acid, is a metal chelator in human milk that is barely detectable in blood serum and below the detection limit in other tissues (6). AMSDH oxidizes 2-AMS to 2-aminomuconate and directs the metabolic flux to enzyme-controlled reactions. We have shown the anticipated enzymatic activity of AMSDH using isolated protein and determined its first crystal structure (5). Furthermore, the binary and ternary complexes as well as two catalytic intermediates, thiohemiacetal and thioacyl, were characterized by soaking single crystals of the binary enzyme-NAD ϩ complex under varied time periods with substrates, widening our knowledge of the catalytic mechanism of this semialdehyde dehydrogenase.

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“…1.2.1.24). Bacterial SSALDHs such as the GabD protein from Escherichia coli (Langendorf et al ., ), Streptococcus pyogenes (SpSSALDH; Jang et al ., ) or cyanobacterium Synechococcus (Park and Rhee, ; Yuan et al ., ) with a preferred NADP + as a coenzyme are classified under the E.C. number 1.2.1.79.…”

Section: Resultsmentioning

confidence: 99%

The ALDH21 gene found in lower plants and some vascular plants codes for a NADP⁺‐dependent succinic semialdehyde dehydrogenase

et al. 2017

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Lower plant species including some green algae, non-vascular plants (bryophytes) as well as the oldest vascular plants (lycopods) and ferns (monilophytes) possess a unique aldehyde dehydrogenase (ALDH) gene named ALDH21, which is upregulated during dehydration. However, the gene is absent in flowering plants. Here, we show that ALDH21 from the moss Physcomitrella patens codes for a tetrameric NADP -dependent succinic semialdehyde dehydrogenase (SSALDH), which converts succinic semialdehyde, an intermediate of the γ-aminobutyric acid (GABA) shunt pathway, into succinate in the cytosol. NAD is a very poor coenzyme for ALDH21 unlike for mitochondrial SSALDHs (ALDH5), which are the closest related ALDH members. Structural comparison between the apoform and the coenzyme complex reveal that NADP binding induces a conformational change of the loop carrying Arg-228, which seals the NADP in the coenzyme cavity via its 2'-phosphate and α-phosphate groups. The crystal structure with the bound product succinate shows that its carboxylate group establishes salt bridges with both Arg-121 and Arg-457, and a hydrogen bond with Tyr-296. While both arginine residues are pre-formed for substrate/product binding, Tyr-296 moves by more than 1 Å. Both R121A and R457A variants are almost inactive, demonstrating a key role of each arginine in catalysis. Our study implies that bryophytes but presumably also some green algae, lycopods and ferns, which carry both ALDH21 and ALDH5 genes, can oxidize SSAL to succinate in both cytosol and mitochondria, indicating a more diverse GABA shunt pathway compared with higher plants carrying only the mitochondrial ALDH5.

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Structural Basis for a Cofactor-dependent Oxidation Protection and Catalysis of Cyanobacterial Succinic Semialdehyde Dehydrogenase

Cited by 17 publications

References 36 publications

Crystal structure of yeast xylose reductase in complex with a novel NADP‐DTT adduct provides insights into substrate recognition and catalysis

Crystal structure of yeast xylose reductase in complex with a novel NADP‐DTT adduct provides insights into substrate recognition and catalysis

A Pitcher-and-Catcher Mechanism Drives Endogenous Substrate Isomerization by a Dehydrogenase in Kynurenine Metabolism

The ALDH21 gene found in lower plants and some vascular plants codes for a NADP⁺‐dependent succinic semialdehyde dehydrogenase

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Structural Basis for a Cofactor-dependent Oxidation Protection and Catalysis of Cyanobacterial Succinic Semialdehyde Dehydrogenase

Cited by 17 publications

References 36 publications

Crystal structure of yeast xylose reductase in complex with a novel NADP‐DTT adduct provides insights into substrate recognition and catalysis

Crystal structure of yeast xylose reductase in complex with a novel NADP‐DTT adduct provides insights into substrate recognition and catalysis

A Pitcher-and-Catcher Mechanism Drives Endogenous Substrate Isomerization by a Dehydrogenase in Kynurenine Metabolism

The ALDH21 gene found in lower plants and some vascular plants codes for a NADP+‐dependent succinic semialdehyde dehydrogenase

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The ALDH21 gene found in lower plants and some vascular plants codes for a NADP⁺‐dependent succinic semialdehyde dehydrogenase