6lhm
From Proteopedia
Structure of human PYCR2
Structural highlights
DiseaseP5CR2_HUMAN PYCR2-related microcephaly-progressive leukoencephalopathy;Autosomal recessive primary microcephaly. The disease is caused by variants affecting the gene represented in this entry. FunctionP5CR2_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 PubMedPatients 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 AlsoReferences
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