Converts alpha-amino-beta-carboxymuconate-epsilon-semialdehyde (ACMS) to alpha-aminomuconate semialdehyde (AMS). ACMS can be converted non-enzymatically to quinolate (QA), a key precursor of NAD, and a potent endogenous excitotoxin of neuronal cells which is implicated in the pathogenesis of various neurodegenerative disorders. In the presence of ACMSD, ACMS is converted to AMS, a benign catabolite. ACMSD ultimately controls the metabolic fate of tryptophan catabolism along the kynurenine pathway.
The enzyme alpha-amino-beta-carboxymuconate-epsilon-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 A 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.
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.
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.
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.
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.
Enzyme that belongs to the lyase family and which catalyzes the spliting of CO(2) from the carboxylic group of amino acids, beta-keto acids and alpha-keto acids.
Enzyme that catalyzes the cleavage of C-C, C-O, C-S, C-N or other bonds by other means than by hydrolysis or oxidation, with two substrates in one reaction direction, and one in the other. In the latter direction, a molecule (of carbon dioxide, water, etc) is eliminated, thus creating a new double bond or a new ring.
A reference proteome is a set of protein sequences derived from a complete proteome which constitutes a defined standard for a particular user community. Reference proteomes are manually defined according to a number of criteria. They cover the proteomes of well- studied model organisms and other proteomes of interest for biomedical and biotechnological research. Reference proteomes have been selected to provide broad coverage of the tree of life, and constitute a representative cross-section of the taxonomic diversity to be found within UniProtKB.
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