Nicotinic Acid Biosynthesis: Control by an Enzyme that Competes with a Spontaneous Reaction

Mehler, Alan H.; Yano, Kunihiko; May, Everette L.

doi:10.1126/science.145.3634.817

Cited by 37 publications

(21 citation statements)

References 6 publications

(1 reference statement)

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“…As shown in Fig. 1, ACMS can be either non‐enzymatically converted into quinolinic acid (QA), fuelling NAD biosynthesis, or transformed by the action of ACMS decarboxylase (ACMSD, also known as picolinate carboxylase; EC 4.1.1.45) into α‐aminomuconic acid‐ε‐semialdehyde, which possibly collapses to picolinic acid (PA) [2,3]. Therefore, by competing with the non‐enzymatic synthesis of QA, ACMSD ultimately controls the metabolic fate of tryptophan catabolism along the kynurenine pathway, and is a medically relevant enzyme in light of the important roles played by QA and PA in physiological and pathological conditions.…”

Section: Introductionmentioning

confidence: 99%

“…acid-e-semialdehyde, which possibly collapses to picolinic acid (PA) [2,3]. Therefore, by competing with the non-enzymatic synthesis of QA, ACMSD ultimately controls the metabolic fate of tryptophan catabolism along the kynurenine pathway, and is a medically relevant enzyme in light of the important roles played by QA and PA in physiological and pathological conditions.…”

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confidence: 99%

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The crystal structure of human α‐amino‐β‐carboxymuconate‐ε‐semialdehyde decarboxylase in complex with 1,3‐dihydroxyacetonephosphate suggests a regulatory link between NAD synthesis and glycolysis

et al. 2009

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The crystal structure of human a-amino-b-carboxymuconatee-semialdehyde decarboxylase in complex with 1,3-dihydroxyacetonephosphate suggests a regulatory link between NAD synthesis and glycolysis The enzyme a-amino-b-carboxymuconate-e-semialdehyde decarboxylase (ACMSD) is a zinc-dependent amidohydrolase that participates in picolinic acid (PA), quinolinic acid (QA) and NAD homeostasis. Indeed, the enzyme stands at a branch point of the tryptophan to NAD pathway, and determines the final fate of the amino acid, i.e. transformation into PA, complete oxidation through the citric acid cycle, or conversion into NAD through QA synthesis. Both PA and QA are key players in a number of physiological and pathological conditions, mainly affecting the central nervous system. As their relative concentrations must be tightly controlled, modulation of ACMSD activity appears to be a promising prospect for the treatment of neurological disorders, including cerebral malaria. Here we report the 2.0 Å resolution crystal structure of human ACMSD in complex with the glycolytic intermediate 1,3-dihydroxyacetonephosphate (DHAP), refined to an R-factor of 0.19. DHAP, which we discovered to be a potent enzyme inhibitor, resides in the ligand binding pocket with its phosphate moiety contacting the catalytically essential zinc ion through mediation of a solvent molecule. Arg47, Asp291 and Trp191 appear to be the key residues for DHAP recognition in human ACMSD. Ligand binding induces a significant conformational change affecting a strictly conserved Trp-Met couple, and we propose that these residues are involved in controlling ligand admission into ACMSD. Our data may be used for the design of inhibitors with potential medical interest, and suggest a regulatory link between de novo NAD biosynthesis and glycolysis.Abbreviations ACMS, a-amino-b-carboxymuconate-e-semialdehyde; ACMSD, a-amino-b-carboxymuconate-e-semialdehyde decarboxylase; DHAP, 1,3-dihydroxyacetonephosphate; PA, picolinic acid; QA, quinolinic acid.

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Section: Introductionmentioning

confidence: 99%

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confidence: 99%

The crystal structure of human α‐amino‐β‐carboxymuconate‐ε‐semialdehyde decarboxylase in complex with 1,3‐dihydroxyacetonephosphate suggests a regulatory link between NAD synthesis and glycolysis

et al. 2009

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“…8–10 In both pathways, ACMSD controls the final fate of the metabolites by competing with a slow spontaneous reaction that produces the excitotoxin quinolinic acid (QA) and directs the metabolic flux away from QA to energy production. 11 QA is an endogenous selective agonist of N -methyl-D-aspartate receptors. 12 It modulates neurotransmission and mediates immune tolerance.…”

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confidence: 99%

Evidence for a Dual Role of an Active Site Histidine in α-Amino-β-carboxymuconate-ε-semialdehyde Decarboxylase

et al. 2012

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The previously reported crystal structures of α-amino-β-carboxymuconate-ε-semialdehyde decarboxylase (ACMSD) show a five-coordinate Zn(II)(His)3(Asp)(OH2) active site. The water ligand is H-bonded to a conserved His228 residue adjacent to the metal center in ACMSD from Pseudomonas fluorescences (PfACMSD). Site directed mutagenesis of His228 to tyrosine and glycine in the present study results in complete or significant loss of activity. Metal analysis shows that H228Y and H228G contain iron rather than zinc, indicating that this residue plays a role in metal selectivity of the protein. As-isolated H228Y displays a blue color, which is not seen in wild-type ACMSD. Quinone staining and resonance Raman analyses indicate that the blue color originates from Fe(III)-tyrosinate ligand-to-metal-charge- transfer (LMCT). Co(II)-substituted H228Y ACMSD is brown in color and exhibits an EPR spectrum showing a high-spin Co(II) center with a well-resolved 59Co (I = 7/2) eight-line hyperfine splitting pattern. The X-ray crystal structures of the as-isolated Fe-H228Y (2.8 Å), Co- (2.4 Å) and Znsubstituted H228Y (2.0 Å resolution) support the spectroscopic assignment of metal ligation of the Tyr228 residue. The crystal structure of Zn-H228G (2.6 Å) was also solved. These four structures show that the water ligand present in WT Zn-ACMSD is either missing (Fe-H228Y, Co-H228Y, and Zn- H228G) or disrupted (Zn-H228Y) in response to His228 mutation. Together, these results highlight the importance of His228 for PfACMSD’s metal specificity as well as maintaining a water molecule as ligand of the metal center. His228 is thus proposed to play a role in activating the metal-bound water ligand for subsequent nucleophilic attack on the substrate.

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“…One endogenous metabolite of L-TRYP catabolism in the KP is PA, which has been reported to possess a wide range of neuro-protective, immunological and antiproliferative affects within the body [5,6]. Another TRYP metabolite, QA is identified as a neurotoxin when its concentrations in the cerebrospinal fluid (CSF) and blood are sufficiently elevated [1,2,4,7]. Hence a reliable and sensitive analytical method need to be developed to quantitate PA and QA concentrations for understanding of their endogenous function in the brain and their potential use as early diagnostic markers for the neurodegenerative diseases.…”

Section: Introductionmentioning

confidence: 99%

Improved separation and detection of picolinic acid and quinolinic acid by capillary electrophoresis-mass spectrometry: Application to analysis of human cerebrospinal fluid

Wang

Davis

Liu

et al. 2013

Journal of Chromatography A

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“Quinolinic acid (QA)”, a metabolite of the kynurenine pathway (KP), is implicated as a major neurological biomarker, which causes inflammatory disorders, whereas there is an increase evidence of the role of picolinic acid (PA) in neuroinflammation. Therefore, there is an urgent need to develop new clinical test for early diagnosis of neuroinflammatory disorders. A comparison is made between three different platforms such as high performance liquid chromatography–electrospray mass spectrometry (HPLC–ESI-MS/MS), nano LC–Chip/ESI-MS/MS, as well as the use of cationic (quaternary ammonium) and anionic (sulfonated) coated capillaries in capillary electrophoresis (CE)-ESI-MS/MS. The comparison revealed that CE-ESI-MS/MS method using a quaternary ammonium coated capillary is the best method for analysis of PA and QA. A simple stacking procedure by the inclusion of acetonitrile in the artificial cerebrospinal fluid (CSF) sample was employed to improve the peak shape and sensitivity of KP metabolites in CE-ESI-MS/MS. The developed CE-ESI-MS/MS assay provided high resolution, high specificity and high sensitivity with a total analysis time including sample preparation of nearly 12 min. In addition, excellent intra-day and inter-day repeatability of migration times and peak areas of the metabolites were observed with respective relative standard deviation (RSD) of less than 2.0% and 2.5%. Somewhat broader variations in repeatability for a 3 independently prepared coated capillary (total 35 runs each) with % RSD up to 3.8% and 5.8% was observed for migration time and peak areas, respectively. Artificial CSF was used as a surrogate matrix to simultaneously generate calibration curves over a concentration range of 0.02–10 μM for PA and 0.4–40 μM for QA. The method was then successfully applied to analyze PA and QA in human CSF, demonstrating the potential of this CE-ESI-MS/MS method to accurately quantitate with high specificity and sensitivity.

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Nicotinic Acid Biosynthesis: Control by an Enzyme that Competes with a Spontaneous Reaction

Cited by 37 publications

References 6 publications

The crystal structure of human α‐amino‐β‐carboxymuconate‐ε‐semialdehyde decarboxylase in complex with 1,3‐dihydroxyacetonephosphate suggests a regulatory link between NAD synthesis and glycolysis

The crystal structure of human α‐amino‐β‐carboxymuconate‐ε‐semialdehyde decarboxylase in complex with 1,3‐dihydroxyacetonephosphate suggests a regulatory link between NAD synthesis and glycolysis

Evidence for a Dual Role of an Active Site Histidine in α-Amino-β-carboxymuconate-ε-semialdehyde Decarboxylase

Improved separation and detection of picolinic acid and quinolinic acid by capillary electrophoresis-mass spectrometry: Application to analysis of human cerebrospinal fluid

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