The Pyridine Ring of NAD Is Formed by a Nonenzymatic Pericyclic Reaction

Colabroy, Keri L.; Begley, Tadhg P.

doi:10.1021/ja0446395

Cited by 55 publications

(41 citation statements)

References 10 publications

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“…During the addition of oxygen, 3-HAA bidentately chelates the active-site iron ion of HAO with its hydroxyl and amino groups, ensuring that the resulting product, 2-amino-3-carboxymuconic semialdehyde (ACMS), will be formed with its two carboxylate groups trans to each other and its amine group cis to its 3-carboxyl group. This much of the stereochemistry has been previously verified (15). A crystal structure of ACMSD bound with a competitive inhibitor also agreed with the two carboxylate groups of ACMS being trans to each other (16).…”

Section: The Catalytic Driving Force Of Isomerization Reaction and Thsupporting

confidence: 74%

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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Section: The Catalytic Driving Force Of Isomerization Reaction and Thsupporting

confidence: 74%

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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“…2-Amino-3-carboxymuconic 6-semialdehyde, the product of the HAD reaction, may either undergo further degradation via 2-aminomuconate 6-semialdehyde or spontaneously cyclize to quinolinate (23) (Fig. 3d).…”

Section: -Hydroxyanthranilate 34-dioxygenase (Had) Is Involved In Tmentioning

confidence: 99%

Ring-Cleaving Dioxygenases with a Cupin Fold

Fetzner

2012

Appl Environ Microbiol

166

141

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ABSTRACTRing-cleaving dioxygenases catalyze key reactions in the aerobic microbial degradation of aromatic compounds. Many pathways converge to catecholic intermediates, which are subject toorthoormetacleavage by intradiol or extradiol dioxygenases, respectively. However, a number of degradation pathways proceed via noncatecholic hydroxy-substituted aromatic carboxylic acids like gentisate, salicylate, 1-hydroxy-2-naphthoate, or aminohydroxybenzoates. The ring-cleaving dioxygenases active toward these compounds belong to the cupin superfamily, which is characterized by a six-stranded β-barrel fold and conserved amino acid motifs that provide the 3His or 2- or 3His-1Glu ligand environment of a divalent metal ion. Most cupin-type ring cleavage dioxygenases use an FeIIcenter for catalysis, and the proposed mechanism is very similar to that of the canonical (type I) extradiol dioxygenases. The metal ion is presumed to act as an electron conduit for single electron transfer from the metal-bound substrate anion to O2, resulting in activation of both substrates to radical species. The family of cupin-type dioxygenases also involves quercetinase (flavonol 2,4-dioxygenase), which opens up two C-C bonds of the heterocyclic ring of quercetin, a wide-spread plant flavonol. Remarkably, bacterial quercetinases are capable of using different divalent metal ions for catalysis, suggesting that the redox properties of the metal are relatively unimportant for the catalytic reaction. The major role of the active-site metal ion could be to correctly position the substrate and to stabilize transition states and intermediates rather than to mediate electron transfer. The tentative hypothesis that quercetinase catalysis involves direct electron transfer from metal-bound flavonolate to O2is supported by model chemistry.

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“…As an example (Scheme 6.13), the biosynthesis of quinolinic acid (65)-a direct precursor of nicotinamide adenine dinucleotide (NAD)-from tryptophan-derived 66 was proposed to take place via acyclic 67 followed by a 6π-electrocyclization (demonstrated with model systems) (Scheme 6.13) [40]. If discovered in secondary metabolism, such a transformation would putatively connect theonelladine-type and cyclostellettamine-type alkaloids via a biosynthetic Zincke-type reaction (cf.…”

Section: Is the Zincke-type Pyridine Ring-opening Biomimetic?mentioning

confidence: 99%