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A functionally atypical amidating enzyme from the human parasite Schistosoma mansoni

GUNNAR R. MAIR^*, MARK J. NICIU, MICHAEL T. STEWART^*, GERRY BRENNAN^*, HANAN OMAR, DAVID W. HALTON^*, RICHARD MAINS, BETTY A. EIPPER, AARON G. MAULE^* and TIM A. DAY^,1

^* Parasitology Research Group, School of Biology and Biochemistry, Queen’s University Belfast, Medical Biology Centre, 97 Lisburn Road, Belfast BT9 7BL, UK;
Department of Neuroscience, University of Connecticut Health Center, Farmington, Connecticut 06030; and
Department of Biomedical Sciences, Veterinary Medicine Building, Iowa State University, Ames, IA 50011, USA

¹Correspondence: Department of Biomedical Sciences, 2036 Veterinary Medicine Building, Iowa State University, Ames, Iowa 50011, USA. E-mail: day{at}iastate.edu

Many neuropeptide transmitters require the presence of a carboxy-terminal -amide group for biological activity. Amidation requires conversion of a glycine-extended peptide intermediate into a C-terminally amidated product. This post-translational modification depends on the sequential action of two enzymes (peptidylglycine -hydroxylating monooxygenase or PHM, and peptidyl--hydroxyglycine -amidating lyase or PAL) that in most eukaryotes are expressed as separate domains of a single protein (peptidylglycine -amidating monooxygenase or PAM). We identified a cDNA encoding PHM in the human parasite Schistosoma mansoni. Transient expression of schistosome PHM (smPHM) revealed functional properties that are different from other PHM proteins; smPHM displays a lower pH-optimum and, when expressed in mammalian cells, is heavily N-glycosylated. In adult worms, PHM is found in the trans-Golgi network and secretory vesicles of both central and peripheral nerves. The widespread occurrence of PHM in the nervous system confirms the important role of amidated neuropeptides in these parasitic flatworms. The differences between schistosome and mammalian PHM suggest that it could be a target for new chemotherapeutics.

Key Words: peptidylglycine alpha-hydroxylating monooxygenase • neuropeptide F • FMRFamide • schistosome • helminth