| Structural highlights
5uat is a 5 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: | NDP, PEG, SO4 |
| Related: | 5uax, 5uaw, 5uav, 5uau |
| Activity: | Pyrroline-5-carboxylate reductase, with EC number 1.5.1.2 |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Disease
[P5CR1_HUMAN] Defects in PYCR1 are the cause of cutis laxa autosomal recessive type 2B (ARCL2B) [MIM:612940]. A multisystem disorder characterized by the appearance of premature aging, wrinkled and lax skin with reduced elasticity, joint laxity, craniofacial dysmorphic features, intrauterine growth retardation with some degree of postnatal growth deficiency, and developmental delay.[1] [2] Defects in PYCR1 are the cause of cutis laxa, autosomal recessive, type 3B (ARCL3B) [MIM:614438]. ARCL3B is a disorder characterized by an aged appearance with distinctive facial features, sparse hair, ophthalmologic abnormalities, intrauterine growth retardation, and cutis laxa.[3] [4]
Function
[P5CR1_HUMAN] Housekeeping enzyme that catalyzes the last step in proline biosynthesis. Can utilize both NAD and NADP, but has higher affinity for NAD. Involved in the cellular response to oxidative stress.[5] [6]
Publication Abstract from PubMed
Pyrroline-5-carboxylate reductase (PYCR) is the final enzyme in proline biosynthesis, catalyzing the NAD(P)H-dependent reduction of Delta1-pyrroline-5-carboxylate (P5C) to proline. Mutations in the PYCR1 gene alter mitochondrial function and cause the connective tissue disorder cutis laxa. Furthermore, PYCR1 is overexpressed in multiple cancers, and the PYCR1 knockout suppresses tumorigenic growth, suggesting PYCR1 is a potential cancer target. However, inhibitor development has been stymied by limited mechanistic details for the enzyme, particularly in light of a previous crystallographic study that placed the cofactor binding site in the C-terminal domain rather than the anticipated Rossmann fold of the N-terminal domain. To fill this gap, we report crystallographic, sedimentation velocity, and kinetics data for human PYCR1. Structures of binary complexes of PYCR1 with NADPH or proline determined at 1.9 A resolution provide insight into cofactor and substrate recognition. We see NADPH bound to the Rossmann fold, over 25 A from the previously proposed site. The 1.85 A resolution structure of a ternary complex containing NADPH and a P5C/proline analog provides a model of the Michaelis complex formed during hydride transfer. Sedimentation velocity shows that PYCR1 forms a concentration-dependent decamer in solution, consistent with the pentamer-of-dimers assembly seen crystallographically. Kinetic and mutational analysis confirmed several features seen in the crystal structure, including the importance of a hydrogen bond between Thr248 and the substrate as well as limited cofactor discrimination.
Resolving the Cofactor Binding Site in the Proline Biosynthetic Enzyme Human Pyrroline-5-Carboxylate Reductase 1.,Christensen EM, Patel SM, Korasick DA, Campbell AC, Krause KL, Becker DF, Tanner JJ J Biol Chem. 2017 Mar 3. pii: jbc.M117.780288. doi: 10.1074/jbc.M117.780288. PMID:28258219[7]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Reversade B, Escande-Beillard N, Dimopoulou A, Fischer B, Chng SC, Li Y, Shboul M, Tham PY, Kayserili H, Al-Gazali L, Shahwan M, Brancati F, Lee H, O'Connor BD, Schmidt-von Kegler M, Merriman B, Nelson SF, Masri A, Alkazaleh F, Guerra D, Ferrari P, Nanda A, Rajab A, Markie D, Gray M, Nelson J, Grix A, Sommer A, Savarirayan R, Janecke AR, Steichen E, Sillence D, Hausser I, Budde B, Nurnberg G, Nurnberg P, Seemann P, Kunkel D, Zambruno G, Dallapiccola B, Schuelke M, Robertson S, Hamamy H, Wollnik B, Van Maldergem L, Mundlos S, Kornak U. Mutations in PYCR1 cause cutis laxa with progeroid features. Nat Genet. 2009 Sep;41(9):1016-21. doi: 10.1038/ng.413. Epub 2009 Aug 2. PMID:19648921 doi:10.1038/ng.413
- ↑ Guernsey DL, Jiang H, Evans SC, Ferguson M, Matsuoka M, Nightingale M, Rideout AL, Provost S, Bedard K, Orr A, Dube MP, Ludman M, Samuels ME. Mutation in pyrroline-5-carboxylate reductase 1 gene in families with cutis laxa type 2. Am J Hum Genet. 2009 Jul;85(1):120-9. doi: 10.1016/j.ajhg.2009.06.008. Epub 2009 , Jul 2. PMID:19576563 doi:10.1016/j.ajhg.2009.06.008
- ↑ Reversade B, Escande-Beillard N, Dimopoulou A, Fischer B, Chng SC, Li Y, Shboul M, Tham PY, Kayserili H, Al-Gazali L, Shahwan M, Brancati F, Lee H, O'Connor BD, Schmidt-von Kegler M, Merriman B, Nelson SF, Masri A, Alkazaleh F, Guerra D, Ferrari P, Nanda A, Rajab A, Markie D, Gray M, Nelson J, Grix A, Sommer A, Savarirayan R, Janecke AR, Steichen E, Sillence D, Hausser I, Budde B, Nurnberg G, Nurnberg P, Seemann P, Kunkel D, Zambruno G, Dallapiccola B, Schuelke M, Robertson S, Hamamy H, Wollnik B, Van Maldergem L, Mundlos S, Kornak U. Mutations in PYCR1 cause cutis laxa with progeroid features. Nat Genet. 2009 Sep;41(9):1016-21. doi: 10.1038/ng.413. Epub 2009 Aug 2. PMID:19648921 doi:10.1038/ng.413
- ↑ Lin DS, Chang JH, Liu HL, Wei CH, Yeung CY, Ho CS, Shu CH, Chiang MF, Chuang CK, Huang YW, Wu TY, Jian YR, Huang ZD, Lin SP. Compound heterozygous mutations in PYCR1 further expand the phenotypic spectrum of De Barsy syndrome. Am J Med Genet A. 2011 Dec;155A(12):3095-9. doi: 10.1002/ajmg.a.34326. Epub 2011 , Nov 3. PMID:22052856 doi:10.1002/ajmg.a.34326
- ↑ Reversade B, Escande-Beillard N, Dimopoulou A, Fischer B, Chng SC, Li Y, Shboul M, Tham PY, Kayserili H, Al-Gazali L, Shahwan M, Brancati F, Lee H, O'Connor BD, Schmidt-von Kegler M, Merriman B, Nelson SF, Masri A, Alkazaleh F, Guerra D, Ferrari P, Nanda A, Rajab A, Markie D, Gray M, Nelson J, Grix A, Sommer A, Savarirayan R, Janecke AR, Steichen E, Sillence D, Hausser I, Budde B, Nurnberg G, Nurnberg P, Seemann P, Kunkel D, Zambruno G, Dallapiccola B, Schuelke M, Robertson S, Hamamy H, Wollnik B, Van Maldergem L, Mundlos S, Kornak U. Mutations in PYCR1 cause cutis laxa with progeroid features. Nat Genet. 2009 Sep;41(9):1016-21. doi: 10.1038/ng.413. Epub 2009 Aug 2. PMID:19648921 doi:10.1038/ng.413
- ↑ Meng Z, Lou Z, Liu Z, Li M, Zhao X, Bartlam M, Rao Z. Crystal structure of human pyrroline-5-carboxylate reductase. J Mol Biol. 2006 Jun 23;359(5):1364-77. Epub 2006 May 11. PMID:16730026 doi:10.1016/j.jmb.2006.04.053
- ↑ Christensen EM, Patel SM, Korasick DA, Campbell AC, Krause KL, Becker DF, Tanner JJ. Resolving the Cofactor Binding Site in the Proline Biosynthetic Enzyme Human Pyrroline-5-Carboxylate Reductase 1. J Biol Chem. 2017 Mar 3. pii: jbc.M117.780288. doi: 10.1074/jbc.M117.780288. PMID:28258219 doi:https://dx.doi.org/10.1074/jbc.M117.780288
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