Proline oxidase
| PRODH | |||
|---|---|---|---|
| Identifiers | |||
Gene ontology | |||
| Molecular function | |||
| Cellular component | |||
| Biological process | |||
| Sources:Amigo / QuickGO | |||
Ensembl | |||||||||
|---|---|---|---|---|---|---|---|---|---|
| UniProt | |||||||||
| RefSeq (mRNA) | |||||||||
| RefSeq (protein) | |||||||||
| Location (UCSC) | Chr 22: 18.91 – 18.94 Mb | Chr 16: 17.88 – 17.91 Mb | |||||||
| PubMed search | [3] | [4] | |||||||
| View/Edit Human | View/Edit Mouse |
Proline dehydrogenase, mitochondrial is an enzyme that in humans is encoded by the PRODH gene.[5][6][7]
The protein encoded by this gene is a
mitochondrial proline dehydrogenase which catalyzes the first step in proline catabolism. Deletion of this gene has been associated with type I hyperprolinemia. The gene is located on chromosome 22q11.21, a region which has also been associated with the contiguous gene deletion syndromes: DiGeorge syndrome and CATCH22 syndrome.[7]
Function
Proline oxidase, or proline dehydrogenase, functions as the initiator of the proline cycle.
rapamycin, stimulated degradation of proline and increased PRODH catalytic activity. Under these conditions PRODH was responsible, at least in part, for maintenance of ATP levels. Activation of AMP-activated protein kinase (AMPK), the cellular energy sensor, by 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR), also markedly upregulated PRODH and increased PRODH-dependent ATP levels, further supporting its role during stress. Glucose deprivation increased intracellular proline levels, and expression of PRODH activated the pentose phosphate pathway. Therefore, the induction of the proline cycle under conditions of nutrient stress may be a mechanism by which cells switch to a catabolic mode for maintaining cellular energy levels.[8]
Clinical significance
Mutations in the PRODH gene are associated with Proline Dehydrogenase deficiency. Many case studies have reported on this genetic disorder. In one such case study, 4 unrelated patients with HPI and a severe neurologic phenotype were shown to have the following common features: psychomotor delay from birth, often associated with hypotonia, severe language delay, autistic features, behavioral problems, and seizures. One patient who was heterozygous for a 22q11 microdeletion also had dysmorphic features. Four previously reported patients with HPI and neurologic involvement had a similar phenotype. This case study showed that Hyperprolinemia, Type I (HPI) may not always be a benign condition, and that the severity of the clinical phenotype appears to correlate with the serum proline level.[9] Still, in another case study, clinical features from 4 unrelated patients included early motor and cognitive developmental delay, speech delay, autistic features, hyperactivity, stereotypic behaviors, and seizures. All patients had increased plasma and urine proline levels. All patients had biallelic mutations in the PRODH gene, often with several variants on the same allele. Residual enzyme activity ranged from null in the most severely affected patient to 25 to 30% in those with a relatively milder phenotype.[10]
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000100033 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000003526 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- S2CID 13473036.
- S2CID 10813774.
- ^ a b "Entrez Gene: PRODH proline dehydrogenase (oxidase) 1".
- PMID 19415679.
- S2CID 43512139.
- S2CID 29894262.
Further reading
- Kempf L, Nicodemus KK, Kolachana B, Vakkalanka R, Verchinski BA, Egan MF, Straub RE, Mattay VA, Callicott JH, Weinberger DR, Meyer-Lindenberg A (Nov 2008). Katsanis N (ed.). "Functional polymorphisms in PRODH are associated with risk and protection for schizophrenia and fronto-striatal structure and function". PLOS Genetics. 4 (11): e1000252. PMID 18989458.
- Polyak K, Xia Y, Zweier JL, Kinzler KW, Vogelstein B (Sep 1997). "A model for p53-induced apoptosis". Nature. 389 (6648): 300–5. S2CID 4429638.
- Donald SP, Sun XY, Hu CA, Yu J, Mei JM, Valle D, Phang JM (Mar 2001). "Proline oxidase, encoded by p53-induced gene-6, catalyzes the generation of proline-dependent reactive oxygen species". Cancer Research. 61 (5): 1810–5. PMID 11280728.
- Liu H, Heath SC, Sobin C, Roos JL, Galke BL, Blundell ML, Lenane M, Robertson B, Wijsman EM, Rapoport JL, Gogos JA, Karayiorgou M (Mar 2002). "Genetic variation at the 22q11 PRODH2/DGCR6 locus presents an unusual pattern and increases susceptibility to schizophrenia". Proceedings of the National Academy of Sciences of the United States of America. 99 (6): 3717–22. PMID 11891283.
- Jacquet H, Raux G, Thibaut F, Hecketsweiler B, Houy E, Demilly C, Haouzir S, Allio G, Fouldrin G, Drouin V, Bou J, Petit M, Campion D, Frébourg T (Sep 2002). "PRODH mutations and hyperprolinemia in a subset of schizophrenic patients". Human Molecular Genetics. 11 (19): 2243–9. PMID 12217952.
- Maxwell SA, Rivera A (Mar 2003). "Proline oxidase induces apoptosis in tumor cells, and its expression is frequently absent or reduced in renal carcinomas". The Journal of Biological Chemistry. 278 (11): 9784–9. PMID 12514185.
- Jacquet H, Berthelot J, Bonnemains C, Simard G, Saugier-Veber P, Raux G, Campion D, Bonneau D, Frebourg T (Jan 2003). "The severe form of type I hyperprolinaemia results from homozygous inactivation of the PRODH gene". Journal of Medical Genetics. 40 (1): 7e–7. PMID 12525555.
- Williams HJ, Williams N, Spurlock G, Norton N, Zammit S, Kirov G, Owen MJ, O'Donovan MC (Jul 2003). "Detailed analysis of PRODH and PsPRODH reveals no association with schizophrenia". American Journal of Medical Genetics Part B. 120B (1): 42–6. S2CID 22741500.
- Li T, Ma X, Sham PC, Sun X, Hu X, Wang Q, Meng H, Deng W, Liu X, Murray RM, Collier DA (Aug 2004). "Evidence for association between novel polymorphisms in the PRODH gene and schizophrenia in a Chinese population". American Journal of Medical Genetics Part B. 129B (1): 13–5. S2CID 43876243.
- Zhang M, White TA, Schuermann JP, Baban BA, Becker DF, Tanner JJ (Oct 2004). "Structures of the Escherichia coli PutA proline dehydrogenase domain in complex with competitive inhibitors". Biochemistry. 43 (39): 12539–48. PMID 15449943.
- Jacquet H, Demily C, Houy E, Hecketsweiler B, Bou J, Raux G, Lerond J, Allio G, Haouzir S, Tillaux A, Bellegou C, Fouldrin G, Delamillieure P, Ménard JF, Dollfus S, D'Amato T, Petit M, Thibaut F, Frébourg T, Campion D (May 2005). "Hyperprolinemia is a risk factor for schizoaffective disorder". Molecular Psychiatry. 10 (5): 479–85. S2CID 21756122.
- Bender HU, Almashanu S, Steel G, Hu CA, Lin WW, Willis A, Pulver A, Valle D (Mar 2005). "Functional consequences of PRODH missense mutations". American Journal of Human Genetics. 76 (3): 409–20. PMID 15662599.
- Rivera A, Maxwell SA (Aug 2005). "The p53-induced gene-6 (proline oxidase) mediates apoptosis through a calcineurin-dependent pathway". The Journal of Biological Chemistry. 280 (32): 29346–54. PMID 15914462.
- Pandhare J, Cooper SK, Phang JM (Jan 2006). "Proline oxidase, a proapoptotic gene, is induced by troglitazone: evidence for both peroxisome proliferator-activated receptor gamma-dependent and -independent mechanisms". The Journal of Biological Chemistry. 281 (4): 2044–52. PMID 16303758.
- Liu Y, Borchert GL, Surazynski A, Hu CA, Phang JM (Sep 2006). "Proline oxidase activates both intrinsic and extrinsic pathways for apoptosis: the role of ROS/superoxides, NFAT and MEK/ERK signaling". Oncogene. 25 (41): 5640–7. PMID 16619034.
- Li D, He L (Oct 2006). "Association study of the G-protein signaling 4 (RGS4) and proline dehydrogenase (PRODH) genes with schizophrenia: a meta-analysis". European Journal of Human Genetics. 14 (10): 1130–5. PMID 16791139.
External links
- Proline+oxidase at the U.S. National Library of Medicine Medical Subject Headings (MeSH)