Publications

• Identification and expression of a cDNA encoding human alpha-amino-beta-carboxymuconate-epsilon-semialdehyde decarboxylase (ACMSD). A key enzyme for the tryptophan-niacine pathway and 'quinolinate hypothesis'.

  Fukuoka S., Ishiguro K., Yanagihara K., Tanabe A., Egashira Y., Sanada H., Shibata K.

  Quinolinate (quinolinic acid) is a potent endogenous excitotoxin of neuronal cells. Elevation of quinolinate levels in the brain has been implicated in the pathogenesis of various neurodegenerative disorders, the so-called "quinolinate hypothesis." Quinolinate is non-enzymatically derived from alp ... >> More

  Quinolinate (quinolinic acid) is a potent endogenous excitotoxin of neuronal cells. Elevation of quinolinate levels in the brain has been implicated in the pathogenesis of various neurodegenerative disorders, the so-called "quinolinate hypothesis." Quinolinate is non-enzymatically derived from alpha-amino-beta-carboxymuconate-epsilon-semialdehyde (ACMS). Alpha-amino-beta-carboxymuconate-epsilon-semialdehyde decarboxylase (ACMSD) is the only known enzyme that can process ACMS to a benign catabolite and thus prevent the accumulation of quinolinate from ACMS. ACMSD seems to be regulated by nutritional and hormonal signals, but its molecular mechanism has, to date, been largely unknown. Utilizing partial amino acid sequences obtained from highly purified porcine kidney ACMSD, a cDNA encoding human ACMSD was cloned and characterized. The cDNA encodes a unique open reading frame of 336 amino acids and displays little homology to any known enzymes or motifs in mammalian databases, suggesting that ACMSD may contain a new kind of protein fold. Real-time PCR-based quantification of ACMSD revealed very low but significant levels of the expression in the brain. Brain ACMSD messages were down- and up-regulated in response to low protein diet and streptozocin-induced diabetes, respectively. The enzyme activities measured from partially purified brains were closely correlated with the changes in the message levels. Expression of quinolinate phosphoribosyltransferase (QPRT), another enzyme that catabolizes quinolinate, was also found in the brain. This suggests that a pathway does exist by which the levels of quinolinate in the brain are regulated. In this report, we address the molecular basis underlying quinolinate metabolism and the regulation of ACMSD expression. << Less

  J. Biol. Chem. 277:35162-35167(2002) [PubMed] [EuropePMC]

• alpha-Amino-beta-carboxymuconate-epsilon-semialdehyde decarboxylase catalyzes enol/keto tautomerization of oxaloacetate.

  Yang Y., Davis I., Altman R.A., Liu A.

  ACMSD (α-amino-β-carboxymuconate-ε-semialdehyde decarboxylase) is a key metalloenzyme critical for regulating de novo endogenous NAD⁺/NADH biosynthesis through the tryptophan-kynurenine pathway. This decarboxylase is a recognized target implicated in mitochondrial diseases and neurodege ... >> More

  ACMSD (α-amino-β-carboxymuconate-ε-semialdehyde decarboxylase) is a key metalloenzyme critical for regulating de novo endogenous NAD⁺/NADH biosynthesis through the tryptophan-kynurenine pathway. This decarboxylase is a recognized target implicated in mitochondrial diseases and neurodegenerative disorders. However, unraveling its enzyme-substrate complex has been challenging due to its high catalytic efficiency. Here, we present a combined biochemical and structural study wherein we determined the crystal structure of ACMSD in complex with malonate. Our analysis revealed significant rearrangements in the active site, particularly in residues crucial for ACMS decarboxylation, including Arg51, Arg239∗ (a residue from an adjacent subunit), His228, and Trp194. Docking modeling studies proposed a putative ACMS binding mode. Additionally, we found that ACMSD catalyzes oxaloacetic acid (OAA) tautomerization at a rate of 6.51 ± 0.42 s^-1 but not decarboxylation. The isomerase activity of ACMSD on OAA warrants further investigation in future biological studies. Subsequent mutagenesis studies and crystallographic analysis of the W194A variant shed light on the roles of specific second-coordination sphere residues. Our findings indicate that Arg51 and Arg239∗ are crucial for OAA tautomerization. Moreover, our comparative analysis with related isomerase superfamily members underscores a general strategy employing arginine residues to promote OAA isomerization. Given the observed isomerase activity of ACMSD on OAA and its structural similarity to ACMS, we propose that ACMSD may facilitate isomerization to ensure ACMS is in the optimal tautomeric form for subsequent decarboxylation initiated by the zinc-bound hydroxide ion. Overall, these findings deepen the understanding of the structure and function of ACMSD, offering insights into potential therapeutic interventions. << Less

  J Biol Chem 300:107878-107878(2024) [PubMed] [EuropePMC]

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