Human carbonyl reductase 4 is a mitochondrial NADPH-dependent quinone reductase.
A protein encoded in the gene Cbr4 on human chromosome 4q32.3 belongs to the short-chain dehydrogenase/reductase family. Contrary to the functional annotation as carbonyl reductase 4 (CBR4), we show that the recombinant tetrameric protein, composed of 25-kDa subunits, exhibits NADPH-dependent reductase activity for o- and p-quinones, but not for other aldehydes and ketones. The enzyme was insensitive to dicumarol and quercetin, potent inhibitors of cytosolic quinone reductases. The 25-kDa CBR4 was detected in human liver, kidney and cell lines on Western blotting using anti-CBR4 antibodies. The overexpression of CBR4 in bovine endothelial cells reveals that the enzyme has a non-cleavable mitochondrial targeting signal. We further demonstrate that the in vitro quinone reduction by CBR4 generates superoxide through the redox cycling, and suggest that the enzyme may be involved in the induction of apoptosis by cytotoxic 9,10-phenanthrenequinone.
Endo
Satoshi
S
Laboratory of Biochemistry, Gifu Pharmaceutical University, 5-6-1 Mitahora-Higashi, Gifu 502-8585, Japan. sendo@gifu-pu.ac.jp
Matsunaga
Toshiyuki
T
Kitade
Yukio
Y
Ohno
Satoshi
S
Tajima
Kazuo
K
El-Kabbani
Ossama
O
Hara
Akira
A
D000595:Amino Acid Sequence; D017209:Apoptosis; D016227:Benzoquinones / Q000737:chemistry / Q000378:metabolism; D002460:Cell Line; D006801:Humans; D024101:Mitochondrial Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D010084:Oxidation-Reduction; D010616:Phenanthrenes / Q000633:toxicity; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D014018:Tissue Distribution
D016227:Benzoquinones; D024101:Mitochondrial Proteins; D010616:Phenanthrenes; D011994:Recombinant Proteins; D013481:Superoxides; C004532:quinone; C005399:9,10-phenanthrenequinone; C533692:CBR4 protein, human; D016660:NAD(P)H Dehydrogenase (Quinone)