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Journal of Biochemistry Advance Access originally published online on September 17, 2008
Journal of Biochemistry 2008 144(5):655-663; doi:10.1093/jb/mvn114
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© 2008 The Japanese Biochemical Society

The Nudix Hydrolase 7 is an Acyl-CoA Diphosphatase Involved in Regulating Peroxisomal Coenzyme A Homeostasis

Sarah-Jayne Reilly1,*, Veronika Tillander1,*, Rob Ofman2, Stefan E.H. Alexson1 and Mary C. Hunt3,{dagger}

1Division of Clinical Chemistry C1-74, Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital at Huddinge, SE-141 86 Stockholm, Sweden; 2Department of Clinical Chemistry, Emma Children's Hospital, Academic Medical Centre, University of Amsterdam, PO Box 22700, 1100 DE Amsterdam, The Netherlands; and 3Department of Genetics, Microbiology and Toxicology, Stockholm University, Arrhenius Laboratory, Svante Arrhenius väg 16F, SE-106 91 Stockholm, Sweden

{dagger}To whom correspondence should be addressed. Tel: +46-8-164162, Fax: +46-8-164315, E-mail: mary.hunt{at}gmt.su.se

Received May 23, 2008; Accepted September 3, 2008


  Abstract

Coenzyme A (CoASH) is an obligate cofactor for lipids undergoing β-oxidation in peroxisomes. Although the peroxisomal membrane appears to be impermeable to CoASH, peroxisomes contain their own pool of CoASH. It is believed that CoASH enters peroxisomes as acyl-CoAs, but it is not known how this pool is regulated. The mouse nudix hydrolase 7 (NUDT7{alpha}) was previously identified in peroxisomes as a CoA-diphosphatase, and therefore suggested to be involved in regulation of peroxisomal CoASH levels. Here we show that mouse NUDT7{alpha} mainly acts as an acyl-CoA diphosphatase, with highest activity towards medium-chain acyl-CoAs, and much lower activity with CoASH. Nudt7{alpha} mRNA is highly expressed in liver, brown adipose tissue and heart, similar to enzymes involved in peroxisomal lipid degradation. Nudt7{alpha} mRNA is down-regulated by Wy-14,643, a peroxisome proliferator-activated receptor {alpha} (PPAR{alpha}) ligand, in a PPAR{alpha}-dependent manner in mouse liver. In highly purified peroxisomes, nudix hydrolase activity is highest with C6-CoA and is decreased by fibrate treatment. Under certain conditions, such as treatment with peroxisome proliferators or fasting, an increase in peroxisomal CoASH levels has been reported, which is in line with a decreased expression/activity of NUDT7{alpha}. Taken together these data suggest that NUDT7{alpha} function is tightly linked to peroxisomal CoASH/acyl-CoA homeostasis.

Key Words: peroxisomes, acyl-CoA thioesterase, peroxisome proliferator-activated receptor-{alpha}, nudix hydrolase, coenzyme A

Abbreviations: Acot, acyl-CoA thioesterase; CoASH, coenzyme A; Nudt, nudix hydrolase; PPAR{alpha}, peroxisome proliferator-activated receptor-{alpha}

*These two authors contributed equally to this work.


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