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1.85-A resolution crystal structure of human ornithine transcarbamoylase complexed with N-phosphonacetyl-L-ornithine. Catalytic mechanism and correlation with inherited deficiency.

Shi D, Morizono H, Ha Y, Aoyagi M, Tuchman M, Allewell NM
J Biol Chem 273 34247-54 (1998)
Cited: 60 times
EuropePMC logo PMID: 9852088

Abstract

The crystal structure of human ornithine transcarbamoylase complexed with the bisubstrate analog N-phosphonacetyl-L-ornithine has been solved at 1.85-A resolution by molecular replacement. Deleterious mutations produce clinical hyperammonia that, if untreated, results in neurological symptoms or death (ornithine transcarbamylase deficiency). The holoenzyme is trimeric, and as in other transcarbamoylases, each subunit contains an N-terminal domain that binds carbamoyl phosphate and a C-terminal domain that binds L-ornithine. The active site is located in the cleft between domains and contains additional residues from an adjacent subunit. Binding of N-phosphonacetyl-L-ornithine promotes domain closure. The resolution of the structure enables the role of active site residues in the catalytic mechanism to be critically examined. The side chain of Cys-303 is positioned so as to be able to interact with the delta-amino group of L-ornithine which attacks the carbonyl carbon of carbamoyl phosphate in the enzyme-catalyzed reaction. This sulfhydryl group forms a charge relay system with Asp-263 and the alpha-amino group of L-ornithine, instead of with His-302 and Glu-310, as previously proposed. In common with other ureotelic ornithine transcarbamoylases, the human enzyme lacks a loop of approximately 20 residues between helix H10 and beta-strand B10 which is present in prokaryotic ornithine transcarbamoylases but has a C-terminal extension of 10 residues that interacts with the body of the protein but is exposed. The sequence of this C-terminal extension is homologous to an interhelical loop found in several membrane proteins, including mitochondrial transport proteins, suggesting a possible mode of interaction with the inner mitochondrial membrane.

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  1. Ornithine Transcarbamylase - From Structure to Metabolism: An Update. Couchet M, Breuillard C, Corne C, Rendu J, Morio B, Schlattner U, Moinard C. Front Physiol 12 748249 (2021)

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  1. Toward better refinement of comparative models: predicting loops in inexact environments. Sellers BD, Zhu K, Zhao S, Friesner RA, Jacobson MP. Proteins 72 959-971 (2008)
  2. Spectrum of disease-causing mutations in protein secondary structures. Khan S, Vihinen M. BMC Struct Biol 7 56 (2007)
  3. Dissecting antibodies with regards to linear and conformational epitopes. Forsström B, Axnäs BB, Rockberg J, Danielsson H, Bohlin A, Uhlen M. PLoS One 10 e0121673 (2015)
  4. Development of a new physics-based internal coordinate mechanics force field and its application to protein loop modeling. Arnautova YA, Abagyan RA, Totrov M. Proteins 79 477-498 (2011)
  5. On the evolutionary conservation of hydrogen bonds made by buried polar amino acids: the hidden joists, braces and trusses of protein architecture. Worth CL, Blundell TL. BMC Evol Biol 10 161 (2010)
  6. Atomic-accuracy prediction of protein loop structures through an RNA-inspired Ansatz. Das R. PLoS One 8 e74830 (2013)
  7. Sudden unexpected fatal encephalopathy in adults with OTC gene mutations-Clues for early diagnosis and timely treatment. Cavicchi C, Donati M, Parini R, Rigoldi M, Bernardi M, Orfei F, Gentiloni Silveri N, Colasante A, Funghini S, Catarzi S, Pasquini E, la Marca G, Mooney S, Guerrini R, Morrone A. Orphanet J Rare Dis 9 105 (2014)
  8. Conformational sampling and structure prediction of multiple interacting loops in soluble and β-barrel membrane proteins using multi-loop distance-guided chain-growth Monte Carlo method. Tang K, Wong SW, Liu JS, Zhang J, Liang J. Bioinformatics 31 2646-2652 (2015)
  9. X-ray structure and kinetic properties of ornithine transcarbamoylase from the human parasite Giardia lamblia. Galkin A, Kulakova L, Wu R, Gong M, Dunaway-Mariano D, Herzberg O. Proteins 76 1049-1053 (2009)
  10. Identified the Synergistic Mechanism of Drynariae Rhizoma for Treating Fracture Based on Network Pharmacology. Lin H, Wang X, Wang L, Dong H, Huang P, Cai Q, Mo Y, Huang F, Jiang Z. Evid Based Complement Alternat Med 2019 7342635 (2019)
  11. Mapping small molecule binding data to structural domains. Kruger FA, Rostom R, Overington JP. BMC Bioinformatics 13 Suppl 17 S11 (2012)
  12. New Deep Learning Methods for Protein Loop Modeling. Nguyen SP, Li Z, Xu D, Shang Y. IEEE/ACM Trans Comput Biol Bioinform 16 596-606 (2019)
  13. Mitochondrial Enzymes of the Urea Cycle Cluster at the Inner Mitochondrial Membrane. Haskins N, Bhuvanendran S, Anselmi C, Gams A, Kanholm T, Kocher KM, LoTempio J, Krohmaly KI, Sohai D, Stearrett N, Bonner E, Tuchman M, Morizono H, Jaiswal JK, Caldovic L. Front Physiol 11 542950 (2020)
  14. Relating the shape of protein binding sites to binding affinity profiles: is there an association? Simon Z, Vigh-Smeller M, Peragovics A, Csukly G, Zahoránszky-Kohalmi G, Rauscher AA, Jelinek B, Hári P, Bitter I, Málnási-Csizmadia A, Czobor P. BMC Struct Biol 10 32 (2010)
  15. New insight into the transcarbamylase family: the structure of putrescine transcarbamylase, a key catalyst for fermentative utilization of agmatine. Polo LM, Gil-Ortiz F, Cantín A, Rubio V. PLoS One 7 e31528 (2012)
  16. Overexpression, purification, crystallization and preliminary structural studies of catabolic ornithine transcarbamylase from Lactobacillus hilgardii. de Las Rivas B, Rodríguez H, Angulo I, Muñoz R, Mancheño JM. Acta Crystallogr Sect F Struct Biol Cryst Commun 63 563-567 (2007)
  17. Computational pipeline to identify and characterize functional mutations in ornithine transcarbamylase deficiency. Magesh R, George Priya Doss C. 3 Biotech 4 621-634 (2014)
  18. Mutation Study of Malaysian Patients with Ornithine Transcarbamylase Deficiency: Clinical, Molecular, and Bioinformatics Analyses of Two Novel Missense Mutations of the OTC Gene. Ali EZ, Zakaria Y, Mohd Radzi MA, Ngu LH, Jusoh SA. Biomed Res Int 2018 4320831 (2018)
  19. The dipeptidyl peptidase IV inhibitors vildagliptin and K-579 inhibit a phospholipase C: a case of promiscuous scaffolds in proteins. Chakraborty S, Rendón-Ramírez A, Ásgeirsson B, Dutta M, Ghosh AS, Oda M, Venkatramani R, Rao BJ, Dandekar AM, Goñi FM. F1000Res 2 286 (2013)
  20. Therapeutic enzyme engineering using a generative neural network. Giessel A, Dousis A, Ravichandran K, Smith K, Sur S, McFadyen I, Zheng W, Licht S. Sci Rep 12 1536 (2022)
  21. Structural analysis and molecular substrate recognition properties of Arabidopsis thaliana ornithine transcarbamylase, the molecular target of phaseolotoxin produced by Pseudomonas syringae. Nielipinski M, Pietrzyk-Brzezinska AJ, Wlodawer A, Sekula B. Front Plant Sci 14 1297956 (2023)


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  2. Mutations and polymorphisms in the human ornithine transcarbamylase gene. Tuchman M, Jaleel N, Morizono H, Sheehy L, Lynch MG. Hum Mutat 19 93-107 (2002)
  3. Genotype-Phenotype Correlations in Ornithine Transcarbamylase Deficiency: A Mutation Update. Caldovic L, Abdikarim I, Narain S, Tuchman M, Morizono H. J Genet Genomics 42 181-194 (2015)
  4. The TB Structural Genomics Consortium: a decade of progress. Chim N, Habel JE, Johnston JM, Krieger I, Miallau L, Sankaranarayanan R, Morse RP, Bruning J, Swanson S, Kim H, Kim CY, Li H, Bulloch EM, Payne RJ, Manos-Turvey A, Hung LW, Baker EN, Lott JS, James MN, Terwilliger TC, Eisenberg DS, Sacchettini JC, Goulding CW. Tuberculosis (Edinb) 91 155-172 (2011)
  5. From Genome to Structure and Back Again: A Family Portrait of the Transcarbamylases. Shi D, Allewell NM, Tuchman M. Int J Mol Sci 16 18836-18864 (2015)
  6. Human carbamoyl phosphate synthetase I (CPSI): insights on the structural role of the unknown function domains. Lopes-Marques M, Igrejas G, Amorim A, Azevedo L. Biochem Biophys Res Commun 421 409-412 (2012)

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  1. Mutations and polymorphisms in the human ornithine transcarbamylase (OTC) gene. Yamaguchi S, Brailey LL, Morizono H, Bale AE, Tuchman M. Hum Mutat 27 626-632 (2006)
  2. Genotype spectrum of ornithine transcarbamylase deficiency: correlation with the clinical and biochemical phenotype. McCullough BA, Yudkoff M, Batshaw ML, Wilson JM, Raper SE, Tuchman M. Am J Med Genet 93 313-319 (2000)
  3. Human ornithine transcarbamylase: crystallographic insights into substrate recognition and conformational changes. Shi D, Morizono H, Yu X, Tong L, Allewell NM, Tuchman M. Biochem J 354 501-509 (2001)
  4. Lysine 88 acetylation negatively regulates ornithine carbamoyltransferase activity in response to nutrient signals. Yu W, Lin Y, Yao J, Huang W, Lei Q, Xiong Y, Zhao S, Guan KL. J Biol Chem 284 13669-13675 (2009)
  5. Acetylornithine transcarbamylase: a novel enzyme in arginine biosynthesis. Morizono H, Cabrera-Luque J, Shi D, Gallegos R, Yamaguchi S, Yu X, Allewell NM, Malamy MH, Tuchman M. J Bacteriol 188 2974-2982 (2006)
  6. Adult-onset ornithine transcarbamylase (OTC) deficiency unmasked by the Atkins' diet. Ben-Ari Z, Dalal A, Morry A, Pitlik S, Zinger P, Cohen J, Fattal I, Galili-Mosberg R, Tessler D, Baruch RG, Nuoffer JM, Largiader CR, Mandel H. J Hepatol 52 292-295 (2010)
  7. Estimation of the total number of disease-causing mutations in ornithine transcarbamylase (OTC) deficiency. Value of the OTC structure in predicting a mutation pathogenic potential. Arranz JA, Riudor E, Marco-Marín C, Rubio V. J Inherit Metab Dis 30 217-226 (2007)
  8. Metabolic enzymes from psychrophilic bacteria: challenge of adaptation to low temperatures in ornithine carbamoyltransferase from Moritella abyssi. Xu Y, Feller G, Gerday C, Glansdorff N. J Bacteriol 185 2161-2168 (2003)
  9. Crystal structure of human ornithine transcarbamylase complexed with carbamoyl phosphate and L-norvaline at 1.9 A resolution. Shi D, Morizono H, Aoyagi M, Tuchman M, Allewell NM. Proteins 39 271-277 (2000)
  10. Crystal structure of a transcarbamylase-like protein from the anaerobic bacterium Bacteroides fragilis at 2.0 A resolution. Shi D, Gallegos R, DePonte J, Morizono H, Yu X, Allewell NM, Malamy M, Tuchman M. J Mol Biol 320 899-908 (2002)
  11. A single mutation in the active site swaps the substrate specificity of N-acetyl-L-ornithine transcarbamylase and N-succinyl-L-ornithine transcarbamylase. Shi D, Yu X, Cabrera-Luque J, Chen TY, Roth L, Morizono H, Allewell NM, Tuchman M. Protein Sci 16 1689-1699 (2007)
  12. Crystal structure of the hexameric catabolic ornithine transcarbamylase from Lactobacillus hilgardii: Structural insights into the oligomeric assembly and metal binding. de Las Rivas B, Fox GC, Angulo I, Ripoll MM, Rodríguez H, Muñoz R, Mancheño JM. J Mol Biol 393 425-434 (2009)
  13. Clinical and mutation analysis of 24 Chinese patients with ornithine transcarbamylase deficiency. Shao Y, Jiang M, Lin Y, Mei H, Zhang W, Cai Y, Su X, Hu H, Li X, Liu L. Clin Genet 92 318-322 (2017)
  14. Structures of N-acetylornithine transcarbamoylase from Xanthomonas campestris complexed with substrates and substrate analogs imply mechanisms for substrate binding and catalysis. Shi D, Yu X, Roth L, Morizono H, Tuchman M, Allewell NM. Proteins 64 532-542 (2006)
  15. The crystal structures of ornithine carbamoyltransferase from Mycobacterium tuberculosis and its ternary complex with carbamoyl phosphate and L-norvaline reveal the enzyme's catalytic mechanism. Sankaranarayanan R, Cherney MM, Cherney LT, Garen CR, Moradian F, James MN. J Mol Biol 375 1052-1063 (2008)
  16. A blue native-PAGE analysis of membrane protein complexes in Clostridium thermocellum. Peng Y, Luo Y, Yu T, Xu X, Fan K, Zhao Y, Yang K. BMC Microbiol 11 22 (2011)
  17. Reversible post-translational carboxylation modulates the enzymatic activity of N-acetyl-L-ornithine transcarbamylase. Li Y, Yu X, Ho J, Fushman D, Allewell NM, Tuchman M, Shi D. Biochemistry 49 6887-6895 (2010)
  18. The clinically variable R40H mutant ornithine carbamoyltransferase shows cytosolic degradation of the precursor protein in CHO cells. Mavinakere M, Morizono H, Shi D, Allewell NM, Tuchman M. J Inherit Metab Dis 24 614-622 (2001)
  19. Expression of wild-type and mutant human ornithine transcarbamylase genes in Chinese hamster ovary cells and lack of dominant negative effect of R141Q and R40H mutants. Augustin L, Mavinakere M, Morizono H, Tuchman M. Pediatr Res 48 842-846 (2000)
  20. Glutathione-supported arsenate reduction coupled to arsenolysis catalyzed by ornithine carbamoyl transferase. Németi B, Gregus Z. Toxicol Appl Pharmacol 239 154-161 (2009)
  21. Late-onset ornithine transcarbamylase deficiency in two families with different mutations in the same codon. Ploechl E, Ploechl W, Stoeckler-Ipsiroglu S, Pokorny H, Wermuth B. Clin Genet 59 111-114 (2001)
  22. Long-term correction of ornithine transcarbamylase deficiency in Spf-Ash mice with a translationally optimized AAV vector. De Sabbata G, Boisgerault F, Guarnaccia C, Iaconcig A, Bortolussi G, Collaud F, Ronzitti G, Sola MS, Vidal P, Rouillon J, Charles S, Nicastro E, D'Antiga L, Ilyinskii P, Mingozzi F, Kishimoto TK, Muro AF. Mol Ther Methods Clin Dev 20 169-180 (2021)
  23. Probing remote residues important for catalysis in Escherichia coli ornithine transcarbamoylase. Ngu L, Winters JN, Nguyen K, Ramos KE, DeLateur NA, Makowski L, Whitford PC, Ondrechen MJ, Beuning PJ. PLoS One 15 e0228487 (2020)
  24. Crystal structure and biochemical properties of putrescine carbamoyltransferase from Enterococcus faecalis: Assembly, active site, and allosteric regulation. Shi D, Yu X, Zhao G, Ho J, Lu S, Allewell NM, Tuchman M. Proteins 80 1436-1447 (2012)
  25. PFstats: A Network-Based Open Tool for Protein Family Analysis. Fonseca-Júnior NJ, Afonso MQL, Oliveira LC, Bleicher L. J Comput Biol 25 480-486 (2018)
  26. Case Reports Late-Onset Ornithine Transcarbamylase Deficiency and Variable Phenotypes in Vietnamese Females With OTC Mutations. Nguyen HH, Khanh Nguyen N, Dung Vu C, Thu Huong Nguyen T, Nguyen NL. Front Pediatr 8 321 (2020)
  27. cDNA cloning of two isoforms of ornithine carbamoyltransferase from Canavalia lineata leaves and the effect of site-directed mutagenesis of the carbamoyl phosphate binding site. Lee Y, Choi YA, Hwang ID, Kim SG, Kwon YM. Plant Mol Biol 46 651-660 (2001)
  28. Comparative structural insight into the unidirectional catalysis of ornithine carbamoyltransferases from Psychrobacter sp. PAMC 21119. Do H, Nguyen DL, Lee CW, Lee MJ, Oh H, Hwang J, Han SJ, Lee SG, Lee JH. PLoS One 17 e0274019 (2022)
  29. In vivo assessment of mutations in OTC for dominant-negative effects following rAAV2/8-mediated gene delivery to the mouse liver. Ginn SL, Cunningham SC, Zheng M, Spinoulas A, Carpenter KH, Alexander IE. Gene Ther 16 820-823 (2009)
  30. Lipid nanoparticle-targeted mRNA formulation as a treatment for ornithine-transcarbamylase deficiency model mice. Yamazaki K, Kubara K, Ishii S, Kondo K, Suzuki Y, Miyazaki T, Mitsuhashi K, Ito M, Tsukahara K. Mol Ther Nucleic Acids 33 210-226 (2023)
  31. Pathogenic variants of ornithine transcarbamylase deficiency: Nation-wide study in Japan and literature review. Kido J, Sugawara K, Sawada T, Matsumoto S, Nakamura K. Front Genet 13 952467 (2022)
  32. The functional impact of 1,570 individual amino acid substitutions in human OTC. Lo RS, Cromie GA, Tang M, Teng K, Owens K, Sirr A, Kutz JN, Morizono H, Caldovic L, Ah Mew N, Gropman A, Dudley AM. Am J Hum Genet 110 863-879 (2023)


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