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4cbs

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X-ray structure of quintuple mutant of human alanine glyoxylate aminotransferase, AGXT_RHEAMX-ray structure of quintuple mutant of human alanine glyoxylate aminotransferase, AGXT_RHEAM

Structural highlights

4cbs is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Activity:Alanine--glyoxylate transaminase, with EC number 2.6.1.44
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

[SPYA_HUMAN] Defects in AGXT are the cause of hyperoxaluria primary type 1 (HP1) [MIM:259900]; also known as primary hyperoxaluria type I (PH1) and oxalosis I. HP1 is a rare autosomal recessive inborn error of glyoxylate metabolism characterized by increased excretion of oxalate and glycolate, and the progressive accumulation of insoluble calcium oxalate in the kidney and urinary tract.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18]

Publication Abstract from PubMed

Protein stability is a fundamental issue in biomedical and biotechnological applications of proteins. Among them, gene- and enzyme-replacement strategies are promising approaches to treat inherited diseases that may benefit from protein engineering techniques, even though these beneficial effects have been largely unexplored. We apply here a sequence-alignment statistics procedure (consensus-based approach) to improve the activity and stability of the human alanine:glyoxylate aminotransferase (AGT) protein, an enzyme which causes primary hyperoxaluria type I (PH1) upon mutation. By combining only five consensus mutations, we obtain a variant (AGT-RHEAM) with largely enhanced in vitro thermal and kinetic stability, increased activity and no side effects on foldability and peroxisomal targeting in mammalian cells. The structure of AGT-RHEAM reveals changes at the dimer interface and improved electrostatic interactions responsible for increased kinetic stability. Consensus-based variants maintain the overall protein fold, crystallized more easily and improve the expression as soluble proteins in two different systems (AGT and CIPK24/SOS2). Thus, the consensus-based approach also emerges as a simple and generic strategy to increase the crystallization success for hard-to-get protein targets as well as to enhance protein stability and function for biomedical applications.

The consensus-based approach for gene/enzyme replacement therapies and crystallization strategies: the case of human alanine:glyoxylate aminotransferase.,Mesa-Torres N, Yunta C, Fabelo-Rosa I, Gonzalez-Rubio JM, Sanchez-Ruiz JM, Salido E, Albert A, Pey AL Biochem J. 2014 Jun 24. PMID:24957194[19]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

See Also

References

  1. ↑ Purdue PE, Takada Y, Danpure CJ. Identification of mutations associated with peroxisome-to-mitochondrion mistargeting of alanine/glyoxylate aminotransferase in primary hyperoxaluria type 1. J Cell Biol. 1990 Dec;111(6 Pt 1):2341-51. PMID:1703535
  2. ↑ Nishiyama K, Funai T, Katafuchi R, Hattori F, Onoyama K, Ichiyama A. Primary hyperoxaluria type I due to a point mutation of T to C in the coding region of the serine:pyruvate aminotransferase gene. Biochem Biophys Res Commun. 1991 May 15;176(3):1093-9. PMID:2039493
  3. ↑ Purdue PE, Lumb MJ, Allsop J, Minatogawa Y, Danpure CJ. A glycine-to-glutamate substitution abolishes alanine:glyoxylate aminotransferase catalytic activity in a subset of patients with primary hyperoxaluria type 1. Genomics. 1992 May;13(1):215-8. PMID:1349575
  4. ↑ Minatogawa Y, Tone S, Allsop J, Purdue PE, Takada Y, Danpur CJ, Kido R. A serine-to-phenylalanine substitution leads to loss of alanine:glyoxylate aminotransferase catalytic activity and immunoreactivity in a patient with primary hyperoxaluria type 1. Hum Mol Genet. 1992 Nov;1(8):643-4. PMID:1301173
  5. ↑ Danpure CJ, Purdue PE, Fryer P, Griffiths S, Allsop J, Lumb MJ, Guttridge KM, Jennings PR, Scheinman JI, Mauer SM, et al.. Enzymological and mutational analysis of a complex primary hyperoxaluria type 1 phenotype involving alanine:glyoxylate aminotransferase peroxisome-to-mitochondrion mistargeting and intraperoxisomal aggregation. Am J Hum Genet. 1993 Aug;53(2):417-32. PMID:8101040
  6. ↑ von Schnakenburg C, Rumsby G. Primary hyperoxaluria type 1: a cluster of new mutations in exon 7 of the AGXT gene. J Med Genet. 1997 Jun;34(6):489-92. PMID:9192270
  7. ↑ von Schnakenburg C, Rumsby G. Identification of new mutations in primary hyperoxaluria type 1 (PH1). J Nephrol. 1998 Mar-Apr;11 Suppl 1:15-7. PMID:9604803
  8. ↑ Amoroso A, Pirulli D, Puzzer D, Ferri L, Crovella S, Ferrettini C, Marangella M, Mazzola G, Florian F. Gene symbol: AGXT. Disease: primary hyperoxaluria type I. Hum Genet. 1999 May;104(5):441. PMID:10394939
  9. ↑ Pirulli D, Puzzer D, Ferri L, Crovella S, Amoroso A, Ferrettini C, Marangella M, Mazzola G, Florian F. Molecular analysis of hyperoxaluria type 1 in Italian patients reveals eight new mutations in the alanine: glyoxylate aminotransferase gene. Hum Genet. 1999 Jun;104(6):523-5. PMID:10453743
  10. ↑ Rinat C, Wanders RJ, Drukker A, Halle D, Frishberg Y. Primary hyperoxaluria type I: a model for multiple mutations in a monogenic disease within a distinct ethnic group. J Am Soc Nephrol. 1999 Nov;10(11):2352-8. PMID:10541294
  11. ↑ Basmaison O, Rolland MO, Cochat P, Bozon D. Identification of 5 novel mutations in the AGXT gene. Hum Mutat. 2000 Jun;15(6):577. PMID:10862087 doi:<577::AID-HUMU9>3.0.CO;2-# 10.1002/1098-1004(200006)15:6<577::AID-HUMU9>3.0.CO;2-#
  12. ↑ Lumb MJ, Danpure CJ. Functional synergism between the most common polymorphism in human alanine:glyoxylate aminotransferase and four of the most common disease-causing mutations. J Biol Chem. 2000 Nov 17;275(46):36415-22. PMID:10960483 doi:10.1074/jbc.M006693200
  13. ↑ Coulter-Mackie MB, Tung A, Henderson HE, Toone JR, Applegarth DA. The AGT gene in Africa: a distinctive minor allele haplotype, a polymorphism (V326I), and a novel PH1 mutation (A112D) in Black Africans. Mol Genet Metab. 2003 Jan;78(1):44-50. PMID:12559847
  14. ↑ Santana A, Salido E, Torres A, Shapiro LJ. Primary hyperoxaluria type 1 in the Canary Islands: a conformational disease due to I244T mutation in the P11L-containing alanine:glyoxylate aminotransferase. Proc Natl Acad Sci U S A. 2003 Jun 10;100(12):7277-82. Epub 2003 May 30. PMID:12777626 doi:10.1073/pnas.1131968100
  15. ↑ van Woerden CS, Groothoff JW, Wijburg FA, Annink C, Wanders RJ, Waterham HR. Clinical implications of mutation analysis in primary hyperoxaluria type 1. Kidney Int. 2004 Aug;66(2):746-52. PMID:15253729 doi:10.1111/j.1523-1755.2004.00796.x
  16. ↑ Monico CG, Olson JB, Milliner DS. Implications of genotype and enzyme phenotype in pyridoxine response of patients with type I primary hyperoxaluria. Am J Nephrol. 2005 Mar-Apr;25(2):183-8. Epub 2005 Apr 21. PMID:15849466 doi:10.1159/000085411
  17. ↑ Frishberg Y, Rinat C, Shalata A, Khatib I, Feinstein S, Becker-Cohen R, Weismann I, Wanders RJ, Rumsby G, Roels F, Mandel H. Intra-familial clinical heterogeneity: absence of genotype-phenotype correlation in primary hyperoxaluria type 1 in Israel. Am J Nephrol. 2005 May-Jun;25(3):269-75. Epub 2005 Jun 15. PMID:15961946 doi:10.1159/000086357
  18. ↑ Coulter-Mackie MB, Lian Q, Applegarth D, Toone J. The major allele of the alanine:glyoxylate aminotransferase gene: nine novel mutations and polymorphisms associated with primary hyperoxaluria type 1. Mol Genet Metab. 2005 Sep-Oct;86(1-2):172-8. Epub 2005 Jun 15. PMID:15963748 doi:10.1016/j.ymgme.2005.05.005
  19. ↑ Mesa-Torres N, Yunta C, Fabelo-Rosa I, Gonzalez-Rubio JM, Sanchez-Ruiz JM, Salido E, Albert A, Pey AL. The consensus-based approach for gene/enzyme replacement therapies and crystallization strategies: the case of human alanine:glyoxylate aminotransferase. Biochem J. 2014 Jun 24. PMID:24957194 doi:http://dx.doi.org/10.1042/BJ20140250

4cbs, resolution 2.30Å

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