The Power of Two

Huo, Lu; Davis, Ian; Chen, Lirong; Liu, Aimin

doi:10.1074/jbc.m113.496869

Cited by 19 publications

(18 citation statements)

References 45 publications

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“…3d ). The moiety that gives rise to this new absorbance band is stable for minutes at room temperature and cannot be separated from the protein by membrane filtration-based methods 20 , suggesting that it is covalently bound to the protein. The formation of an enzyme–substrate adduct in the E268A mutant was investigated by mass spectrometry.…”

Section: Resultsmentioning

confidence: 99%

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Crystallographic and spectroscopic snapshots reveal a dehydrogenase in action

et al. 2015

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Aldehydes are ubiquitous intermediates in metabolic pathways and their innate reactivity can often make them quite unstable. There are several aldehydic intermediates in the metabolic pathway for tryptophan degradation that can decay into neuroactive compounds that have been associated with numerous neurological diseases. An enzyme of this pathway, 2-aminomuconate-6-semialdehyde dehydrogenase, is responsible for ‘disarming’ the final aldehydic intermediate. Here we show the crystal structures of a bacterial analogue enzyme in five catalytically relevant forms: resting state, one binary and two ternary complexes, and a covalent, thioacyl intermediate. We also report the crystal structures of a tetrahedral, thiohemiacetal intermediate, a thioacyl intermediate and an NAD+-bound complex from an active site mutant. These covalent intermediates are characterized by single-crystal and solution-state electronic absorption spectroscopy. The crystal structures reveal that the substrate undergoes an E/Z isomerization at the enzyme active site before an sp3-to-sp2 transition during enzyme-mediated oxidation.

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Section: Resultsmentioning

confidence: 99%

“…ACMS was generated by catalysing the insertion of molecular oxygen to 3-hydroxyanthranilic acid by purified, Fe 2+ reconstituted 3-hydroxyanthranilate 3,4-dioxygenase as described previously 16 20 . 2-HMS is generated non-enzymatically from ACMS following a previously established method 24 .…”

Section: Methodsmentioning

confidence: 99%

Crystallographic and spectroscopic snapshots reveal a dehydrogenase in action

et al. 2015

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“…The X-ray crystal structure of this enzyme was recently solved, and biochemical work has shown a potential mechanism for regulating the activity of this enzyme. It was shown that only the homo-dimer form of ACMSD is able to catalyze the decarboxylation of the substrate, opening the door to the possibility that modulation of the quaternary structure of ACMSD may be the dominant regulatory mechanism for this enzyme [19, 20]. Another interesting feature of ACMSD is that both its substrate and its product are unstable and will undergo electrocyclizations to QUIN and picolinic acid, respectively.…”

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confidence: 99%

“…Answering this question will require detailed knowledge of the enzymatic mechanism of HAO, ACMSD, and the next enzyme in the pathway, α-aminomuconate-ε-semialdehyde dehydrogenase (AMSDH). The structure and mechanism of ACMSD are relatively well studied [19, 20], and the structure of HAO is defined [23]. However, little was known about this third enzyme, which presumably controls the partitioning between further metabolism and picolinic acid formation, until very recently, when the crystal structure was solved, and catalytic mechanism proposed [22].…”

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What is the tryptophan kynurenine pathway and why is it important to neurotherapeutics?

Davis

Liu

2015

Expert Review of Neurotherapeutics

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127

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The kynurenine pathway has received increasing attention as its connection to inflammation, the immune system, and neurological conditions became more apparent. It is the primary route for tryptophan catabolism in the liver and the starting point for the synthesis of nicotinamide adenine dinucleotide in mammals. Dysregulation or overactivation of this pathway can lead to immune system activation and accumulation of potentially neurotoxic compounds. These aspects make the kynurenine pathway a promising target for therapeutic development to treat inflammation and some diseases with neurological aspects, especially in cancer patients undergoing chemotherapy.

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“…On the other hand, docking analysis revealed that carboxyl and hydroxyl groups of 2H1NA are hydrogen bonded with Arg33/Tyr272 and Tyr272 of HndA, respectively. Interestingly, the importance of the arginine residue in substrate binding via carboxylate group has been suggested in ACMSD (33,48). Similarly, the role of the active-site tyrosine residue in the binding of the hydroxyl group of lactic acid was studied in flavocytochrome b 2 or L-lactate dehydrogenase, and it was reported to play a role in converting lactic acid to pyruvic acid (49).…”

Section: Discussionmentioning

confidence: 99%

Functional Characterization of a Novel Member of the Amidohydrolase 2 Protein Family, 2-Hydroxy-1-Naphthoic Acid Nonoxidative Decarboxylase from Burkholderia sp. Strain BC1

et al. 2016

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The gene encoding a nonoxidative decarboxylase capable of catalyzing the transformation of 2-hydroxy-1-naphthoic acid (2H1NA) to 2-naphthol was identified, recombinantly expressed, and purified to homogeneity. The putative gene sequence of the decarboxylase (hndA) encodes a 316-amino-acid protein (HndA) with a predicted molecular mass of 34 kDa. HndA exhibited high identity with uncharacterized amidohydrolase 2 proteins of various Burkholderia species, whereas it showed a modest 27% identity with ␥-resorcylate decarboxylase, a well-characterized nonoxidative decarboxylase belonging to the amidohydrolase superfamily. Biochemically characterized HndA demonstrated strict substrate specificity toward 2H1NA, whereas inhibition studies with HndA indicated the presence of zinc as the transition metal center, as confirmed by atomic absorption spectroscopy. A three-dimensional structural model of HndA, followed by docking analysis, identified the conserved metal-coordinating and substrate-binding residues, while their importance in catalysis was validated by site-directed mutagenesis. IMPORTANCEMicrobial nonoxidative decarboxylases play a crucial role in the metabolism of a large array of carboxy aromatic chemicals released into the environment from a variety of natural and anthropogenic sources. Among these, hydroxynaphthoic acids are usually encountered as pathway intermediates in the bacterial degradation of polycyclic aromatic hydrocarbons. The present study reveals biochemical and molecular characterization of a 2-hydroxy-1-naphthoic acid nonoxidative decarboxylase involved in an alternative metabolic pathway which can be classified as a member of the small repertoire of nonoxidative decarboxylases belonging to the amidohydrolase 2 family of proteins. The strict substrate specificity and sequence uniqueness make it a novel member of the metallo-dependent hydrolase superfamily. Decarboxylase is one of the most important classes of enzymes involved in a large variety of catabolic and anabolic pathways. The majority of the decarboxylases utilize an organic cofactor or a transition metal coupled with dioxygen to activate their substrates leading to the removal of carbon dioxide (1). However, there is a small group of transition metal-dependent decarboxylases that carry out decarboxylation of various aromatic acids in a nonoxidative manner. These nonoxidative decarboxylases act on various lignin-derived compounds, such as 4-hydroxybenzoic acid (2), (carboxy)vanillic acid (3, 4), protocatechuic acid (5), ferulic acid (6), p-coumaric acid (7), and estrogenic phthalate (8). Likewise, oxygen-independent decarboxylases are also involved in the 2-nitrobenzoic acid degradation pathway (9, 10), the tryptophan catabolic pathway (11), and the thymidine salvage pathway (12).Nonoxidative decarboxylases, in general, can broadly be classified into two major groups depending on their oxygen sensitivity. Oxygen-sensitive decarboxylases, viz., 4-hydroxybenzoate decarboxylase (2), 3,4-dihydroxybenzoate decarboxylase (5), and indol...

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The Power of Two

Cited by 19 publications

References 45 publications

Crystallographic and spectroscopic snapshots reveal a dehydrogenase in action

Crystallographic and spectroscopic snapshots reveal a dehydrogenase in action

What is the tryptophan kynurenine pathway and why is it important to neurotherapeutics?

Functional Characterization of a Novel Member of the Amidohydrolase 2 Protein Family, 2-Hydroxy-1-Naphthoic Acid Nonoxidative Decarboxylase from Burkholderia sp. Strain BC1

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