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J. Biol. Chem., Vol. 277, Issue 38, 35162-35167, September 20, 2002

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Identification and Expression of a cDNA Encoding Human -Amino--carboxymuconate--semialdehyde Decarboxylase (ACMSD)
A KEY ENZYME FOR THE TRYPTOPHAN-NIACINE PATHWAY AND "QUINOLINATE HYPOTHESIS"^*

Shin-Ichi Fukuoka^§, Kanako Ishiguro, Kazumi Yanagihara, Atsushi Tanabe^¶, Yukari Egashira^¶, Hiroo Sanada^¶, and Katsumi Shibata

From the  Graduate School of Agriculture, Kyoto University, Uji, Kyoto 611-0011, Japan, the ^¶ Graduate School of Science and Technology, Chiba University, Matsudo, Chiba 271-8510, Japan, and the  Department of Life Style Studies School of Human Cultures, the University of Shiga Prefecture, Hikone, Shiga 522-8533, Japan

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 -amino--carboxymuconate--semialdehyde (ACMS). -Amino--carboxymuconate--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.

The nucleotide sequences of cloned ACMSD cDNAs for human, mouse, C. elegans, and rat reported in this paper have been submitted to GenBank^TM/EBI Data Bank with the accession numbers AB07418, AB07419, AB07420, and AB069781, respectively.

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