Sepiapterin reductase explained

Sepiapterin reductase is an enzyme that in humans is encoded by the SPR gene.^{[1] [2] [3]}

Function

Sepiapterin reductase (7,8-dihydrobiopterin:NADP⁺ oxidoreductase; EC 1.1.1.153) catalyzes the NADPH-dependent reduction of various carbonyl substances, including derivatives of pteridines, and belongs to a group of enzymes called aldo-keto reductases. SPR plays an important role in the biosynthesis of tetrahydrobiopterin.

Reaction

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sepiapterin reductase
Ec Number:	1.1.1.153
Go Code:	0004757
Width:	270

Sepiapterin reductase (SPR) catalyzes the chemical reaction

L-erythro-7,8-dihydrobiopterin + NADP+

\rightleftharpoons sepiapterin + NADPH + H+

Thus, the two substrates of this enzyme are L-erythro-7,8-dihydrobiopterin and NADP⁺, whereas its three products are sepiapterin, NADPH, and a single hydrogen ion (H⁺).

This enzyme belongs to the family of oxidoreductases, to be specific, those acting on the CH-OH group of donor with NAD⁺ or NADP⁺ as acceptor. The systematic name of this enzyme class is 7,8-dihydrobiopterin:NADP⁺ oxidoreductase. This enzyme participates in folate biosynthesis.

^[4]

Clinical significance

Mutations of the SPR gene may cause sepiapterin reductase deficiency, a rare disease. The clinical phenotype can include progressive psychomotor retardation, altered tone, seizures, choreoathetosis, temperature instability, hypersalivation, microcephaly, and irritability. Patients with sepiapterin reductase deficiency also manifest dystonia with diurnal variation, oculogyric crises, tremor, hypersomnolence, oculomotor apraxia, and weakness.^[5] Response to treatment is variable and the long-term and functional outcome is unknown. To provide a basis for improving the understanding of the epidemiology, genotype/phenotype correlation and outcome of these diseases their impact on the quality of life of patients, and for evaluating diagnostic and therapeutic strategies a patient registry was established by the noncommercial International Working Group on Neurotransmitter Related Disorders (iNTD).^[6]

Further reading

• Katoh S . 1971 . Sepiapterin Reductase from Horse Liver: Purification and Properties of the Enzyme. . Arch. Biochem. Biophys. . 146 . 202–214 . 10.1016/S0003-9861(71)80057-7 . 4401291 . 1 .
• Matsubara M, Katoh S, Akino M, Kaufman S . 1966 . Sepiapterin Reductase. . Biochim. Biophys. Acta . 122 . 202–212 . 5969298 . 2 . 10.1016/0926-6593(66)90062-2.
• Takikawa S . Biosynthesis of tetrahydrobiopterin. Purification and characterization of 6-pyruvoyl-tetrahydropterin synthase from human liver . Eur. J. Biochem. . 161 . 2 . 295–302 . 1987 . 3536512 . 10.1111/j.1432-1033.1986.tb10446.x . Curtius HC . Redweik U . Leimbacher . Walter . Ghisla . Sandro . free .
• Thöny B, Heizmann CW, Mattei MG . Human GTP-cyclohydrolase I gene and sepiapterin reductase gene map to region 14q21-q22 and 2p14-p12, respectively, by in situ hybridization . Genomics . 26 . 1 . 168–170 . 1995 . 7782081 . 10.1016/0888-7543(95)80101-Q .
• Maruyama K, Sugano S . Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides . Gene . 138 . 1–2 . 171–174 . 1994 . 8125298 . 10.1016/0378-1119(94)90802-8 .
• Book: Maier J . 338 . 195–8 . 8304109 . 10.1007/978-1-4615-2960-6_39. Schott K . Werner T . Bacher . A . Ziegler . I . Chemistry and Biology of Pteridines and Folates . Northern Blot Analysis of Sepiapterin Reductase mRNA in Mammalian Cell Lines and Tissues . Advances in Experimental Medicine and Biology . 1993 . 978-1-4613-6287-6 .
• Maier J . Detection of a novel sepiapterin reductase mRNA: assay of mRNA in various cells and tissues of various species . Exp. Cell Res. . 204 . 2 . 217–222 . 1993 . 8440319 . 10.1006/excr.1993.1027 . Schott K . Werner T . Bacher . A . Ziegler . I .
• Suzuki Y . Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library . Gene . 200 . 1–2 . 149–156 . 1997 . 9373149 . 10.1016/S0378-1119(97)00411-3 . Yoshitomo-Nakagawa K . Maruyama K . Suyama . A . Sugano . S .
• Blau N . Dihydropteridine reductase deficiency localized to the central nervous system . J. Inherit. Metab. Dis. . 21 . 4 . 433–434 . 1998 . 9700606 . 10.1023/A:1005327313348 . Thöny B . Renneberg A . Arnold . L. A. . Hyland . K. . 20969872 .
• Ohye T . Genomic organization and chromosomal localization of the human sepiapterin reductase gene . Biochem. Biophys. Res. Commun. . 251 . 2 . 597–602 . 1998 . 9792819 . 10.1006/bbrc.1998.9503 . Hori TA . Katoh S . Nagatsu . T . Ichinose . H .
• Blau N . Variant of dihydropteridine reductase deficiency without hyperphenylalaninaemia: effect of oral phenylalanine loading . J. Inherit. Metab. Dis. . 22 . 3 . 216–220 . 1999 . 10384371 . 10.1023/A:1005584627797 . Thöny B . Renneberg A . Penzien . J. M. . Hyland . K. . Hoffmann . G. F. . 30670124 .
• Bonafé L . Mutations in the sepiapterin reductase gene cause a novel tetrahydrobiopterin-dependent monoamine-neurotransmitter deficiency without hyperphenylalaninemia . Am. J. Hum. Genet. . 69 . 2 . 269–277 . 2001 . 11443547 . 10.1086/321970 . 1235302 . Thöny B . Penzien JM . Czarnecki . Barbara . Blau . Nenad .
• Fujimoto K, Takahashi SY, Katoh S . Mutational analysis of sites in sepiapterin reductase phosphorylated by Ca²⁺/calmodulin-dependent protein kinase II . Biochim. Biophys. Acta . 1594 . 1 . 191–8 . 2002 . 11825621 . 10.1016/S0167-4838(01)00300-4 .
• Strausberg RL . Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences . Proc. Natl. Acad. Sci. U.S.A. . 99 . 26 . 16899–16903 . 2003 . 12477932 . 10.1073/pnas.242603899 . 139241 . Feingold EA . Grouse LH . Derge . JG . Klausner . RD . Collins . FS . Wagner . L . Shenmen . CM . Schuler . GD . 2002PNAS...9916899M . free .
• Franscini N . Functional tetrahydrobiopterin synthesis in human platelets . Circulation . 110 . 2 . 186–192 . 2005 . 15197144 . 10.1161/01.CIR.0000134281.82972.57 . Bachli EB . Blau N . Fischler . M . Walter . RB . Schaffner . A . Schoedon . G . free .
• Steinberger D . Heterozygous mutation in 5'-untranslated region of sepiapterin reductase gene (SPR) in a patient with dopa-responsive dystonia . Neurogenetics . 5 . 3 . 187–190 . 2005 . 15241655 . 10.1007/s10048-004-0182-3 . Blau N . Goriuonov D . Bitsch . Juliane . Zuker . Michael . Hummel . Sibylla . Müller . Ulrich . 4833737 .
• Gerhard DS . The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC) . Genome Res. . 14 . 10B . 2121–2127 . 2004 . 15489334 . 10.1101/gr.2596504 . 528928 . Wagner L . Feingold EA . Shenmen . CM . Grouse . LH . Schuler . G . Klein . SL . Old . S . Rasooly . R .
• Sharma M . The sepiapterin reductase gene region reveals association in the PARK3 locus: analysis of familial and sporadic Parkinson's disease in European populations . J. Med. Genet. . 43 . 7 . 557–562 . 2006 . 16443856 . 10.1136/jmg.2005.039149 . 2593029 . Mueller JC . Zimprich A . Lichtner . P . Hofer . A . Leitner . P . Maass . S . Berg . D . Dürr . A .
• Farrugia R . Molecular genetics of tetrahydrobiopterin (BH4) deficiency in the Maltese population . Mol. Genet. Metab. . 90 . 3 . 277–283 . 2007 . 17188538 . 10.1016/j.ymgme.2006.10.013 . Scerri CA . Montalto SA . Parascandolo . Raymond . Neville . Brian G.R. . Felice . Alex E. .
• Tobin JE . Sepiapterin reductase expression is increased in Parkinson's disease brain tissue . Brain Res. . 1139 . 42–47 . 2007 . 17270157 . 10.1016/j.brainres.2007.01.001 . 1868471 . Cui J . Wilk JB . Latourelle . J . Laramie . J . McKee . A . Guttman . M . Karamohamed . S . Destefano . A .

Notes and References

1. Ichinose H, Katoh S, Sueoka T, Titani K, Fujita K, Nagatsu T . Cloning and sequencing of cDNA encoding human sepiapterin reductase--an enzyme involved in tetrahydrobiopterin biosynthesis . Biochem Biophys Res Commun . 179 . 1 . 183–189 . Oct 1991 . 1883349 . 10.1016/0006-291X(91)91352-D .
2. Persson B, Kallberg Y, Bray JE, Bruford E, Dellaporta SL, Favia AD, Duarte RG, Jornvall H, Kavanagh KL, Kedishvili N, Kisiela M, Maser E, Mindnich R, Orchard S, Penning TM, Thornton JM, Adamski J, Oppermann U . The SDR (short-chain dehydrogenase/reductase and related enzymes) nomenclature initiative . Chem Biol Interact . 178 . 1–3 . 94–98 . Feb 2009 . 19027726 . 2896744. 10.1016/j.cbi.2008.10.040 . 2009CBI...178...94P .
3. Web site: Entrez Gene: SPR sepiapterin reductase (7,8-dihydrobiopterin:NADP⁺ oxidoreductase).
4. Web site: BRENDA - Information on EC 1.1.1.153 - sepiapterin reductase (L-erythro-7,8-dihydrobiopterin forming).
5. Pearl PL, Taylor JL, Trzcinski S, Sokohl A . The pediatric neurotransmitter disorders. J Child Neurol. 22. 5. 606–616. May 2007. 17690069. 10.1177/0883073807302619. 10689202.
6. Web site: Patient registry.