| Structural highlights
Disease
P5CR2_HUMAN PYCR2-related microcephaly-progressive leukoencephalopathy;Autosomal recessive primary microcephaly. The disease is caused by variants affecting the gene represented in this entry.
Function
P5CR2_HUMAN Housekeeping enzyme that catalyzes the last step in proline biosynthesis. In some cell types, such as erythrocytes, its primary function may be the generation of NADP(+). Can utilize both NAD and NADP. Has higher affinity for NADP, but higher catalytic efficiency with NADH (PubMed:2722838, PubMed:6894153). Involved in cellular response to oxidative stress (PubMed:25865492).[1] [2] [3]
Publication Abstract from PubMed
Patients lacking PYCR2, a mitochondrial enzyme that synthesizes proline, display postnatal degenerative microcephaly with hypomyelination. Here we report the crystal structure of the PYCR2 apo-enzyme and show that a novel germline p.Gly249Val mutation lies at the dimer interface and lowers its enzymatic activity. We find that knocking out Pycr2 in mice phenocopies the human disorder and depletes PYCR1 levels in neural lineages. In situ quantification of neurotransmitters in the brains of PYCR2 mutant mice and patients revealed a signature of encephalopathy driven by excessive cerebral glycine. Mechanistically, we demonstrate that loss of PYCR2 upregulates SHMT2, which is responsible for glycine synthesis. This hyperglycemia could be partially reversed by SHMT2 knockdown, which rescued the axonal beading and neurite lengths of cultured Pycr2 knockout neurons. Our findings identify the glycine metabolic pathway as a possible intervention point to alleviate the neurological symptoms of PYCR2-mutant patients.
Loss of PYCR2 Causes Neurodegeneration by Increasing Cerebral Glycine Levels via SHMT2.,Escande-Beillard N, Loh A, Saleem SN, Kanata K, Hashimoto Y, Altunoglu U, Metoska A, Grandjean J, Ng FM, Pomp O, Baburajendran N, Wong J, Hill J, Beillard E, Cozzone P, Zaki M, Kayserili H, Hamada H, Shiratori H, Reversade B Neuron. 2020 Jul 8;107(1):82-94.e6. doi: 10.1016/j.neuron.2020.03.028. Epub 2020 , Apr 23. PMID:32330411[4]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Nakayama T, Al-Maawali A, El-Quessny M, Rajab A, Khalil S, Stoler JM, Tan WH, Nasir R, Schmitz-Abe K, Hill RS, Partlow JN, Al-Saffar M, Servattalab S, LaCoursiere CM, Tambunan DE, Coulter ME, Elhosary PC, Gorski G, Barkovich AJ, Markianos K, Poduri A, Mochida GH. Mutations in PYCR2, Encoding Pyrroline-5-Carboxylate Reductase 2, Cause Microcephaly and Hypomyelination. Am J Hum Genet. 2015 May 7;96(5):709-19. doi: 10.1016/j.ajhg.2015.03.003. Epub, 2015 Apr 9. PMID:25865492 doi:http://dx.doi.org/10.1016/j.ajhg.2015.03.003
- ↑ Merrill MJ, Yeh GC, Phang JM. Purified human erythrocyte pyrroline-5-carboxylate reductase. Preferential oxidation of NADPH. J Biol Chem. 1989 Jun 5;264(16):9352-8 PMID:2722838
- ↑ Yeh GC, Harris SC, Phang JM. Pyrroline-5-carboxylate reductase in human erythrocytes. J Clin Invest. 1981 Apr;67(4):1042-6. PMID:6894153 doi:10.1172/jci110115
- ↑ Escande-Beillard N, Loh A, Saleem SN, Kanata K, Hashimoto Y, Altunoglu U, Metoska A, Grandjean J, Ng FM, Pomp O, Baburajendran N, Wong J, Hill J, Beillard E, Cozzone P, Zaki M, Kayserili H, Hamada H, Shiratori H, Reversade B. Loss of PYCR2 Causes Neurodegeneration by Increasing Cerebral Glycine Levels via SHMT2. Neuron. 2020 Jul 8;107(1):82-94.e6. PMID:32330411 doi:10.1016/j.neuron.2020.03.028
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