Identification and expression of alpha cDNA encoding human 2-amino-3-carboxymuconate-6-semialdehyde decarboxylase (ACMSD): a key enzyme for the tryptophan-niacine pathway and quinolinate hypothesis.
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 2-amino-3-carboxymuconate-6-semialdehyde (ACMS). 2-amino-3-carboxymuconate-6-semialdehyde decarboxylase (ACMSD) is the only known enzyme which 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 was down- and up-regulated in response to low protein diet and streptozocin-induced diabetes, respectively. Expression of QPRT, another enzyme which 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.
Fukuoka
Shin-Ichi
S
Graduate School of Agriculuture, Kyoto University, Uji, Kyoto 611-0011, Japan. fukuoka@food2.food.kyoto-u.ac.jp
Ishiguro
Kanako
K
Tanabe
Atsushi
A
Egashira
Yukari
Y
Sanada
Hiroo
H
Fukuwatari
Tsutomu
T
Shibata
Katsumi
K
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D019556:COS Cells; D002262:Carboxy-Lyases / Q000235:genetics* / Q000378:metabolism*; D003001:Cloning, Molecular; D018076:DNA, Complementary / Q000235:genetics*; D015870:Gene Expression; D006801:Humans; D008954:Models, Biological; D008969:Molecular Sequence Data; D009525:Niacin / Q000378:metabolism*; D017378:Quinolinic Acid / Q000378:metabolism*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D014162:Transfection; D014364:Tryptophan / Q000378:metabolism*
D018076:DNA, Complementary; D011994:Recombinant Proteins; D009525:Niacin; D014364:Tryptophan; D002262:Carboxy-Lyases; C024396:aminocarboxymuconate-semialdehyde decarboxylase; D017378:Quinolinic Acid