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Journal of Biochemistry Advance Access published online on September 17, 2008
Journal of Biochemistry, 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,#

1Karolinska Institutet, Department of Laboratory Medicine, Division of Clinical Chemistry C1-74, 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.
3Department of Genetics, Microbiology and Toxicology, Stockholm University, Arrhenius Laboratory, Svante Arrhenius väg 16F, SE-106 91 Stockholm, Sweden.

#Corresponding author: Dr. Mary C. Hunt, Stockholm University, Department of Genetics, Microbiology and Toxicology, Arrhenius Laboratories for the Natural Sciences, Svante Arrhenius väg 16 E & F, SE-106 91 Stockholm,Sweden, Telephone: +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 downregulated 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

*Equal contribution by authors


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