4l3v: Difference between revisions

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New page: '''Unreleased structure''' The entry 4l3v is ON HOLD Authors: Ereno, J., Majtan, T., Oyenarte, I., Kraus, J.P., Martinez, L.A. Description: Crystal Structure of Human Cystathionine Bet...
 
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'''Unreleased structure'''


The entry 4l3v is ON HOLD
==Crystal structure of delta516-525 human cystathionine beta-synthase==
<StructureSection load='4l3v' size='340' side='right'caption='[[4l3v]], [[Resolution|resolution]] 3.63&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[4l3v]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4L3V OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4L3V FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 3.628&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene>, <scene name='pdbligand=PLP:PYRIDOXAL-5-PHOSPHATE'>PLP</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4l3v FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4l3v OCA], [https://pdbe.org/4l3v PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4l3v RCSB], [https://www.ebi.ac.uk/pdbsum/4l3v PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4l3v ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/CBS_HUMAN CBS_HUMAN] Defects in CBS are the cause of cystathionine beta-synthase deficiency (CBSD) [MIM:[https://omim.org/entry/236200 236200]. CBSD is an enzymatic deficiency resulting in altered sulfur metabolism and homocystinuria. The clinical features of untreated homocystinuria due to CBS deficiency include myopia, ectopia lentis, mental retardation, skeletal anomalies resembling Marfan syndrome, and thromboembolic events. Light skin and hair can also be present. Biochemical features include increased urinary homocystine and methionine.<ref>PMID:1301198</ref> <ref>PMID:8353501</ref> <ref>PMID:7506602</ref> <ref>PMID:7981678</ref> <ref>PMID:7849717</ref> <ref>PMID:7967489</ref> <ref>PMID:7611293</ref> <ref>PMID:7762555</ref> <ref>PMID:7635485</ref> <ref>PMID:8528202</ref> <ref>PMID:7564249</ref> <ref>PMID:8755636</ref> <ref>PMID:8803779</ref> <ref>PMID:9156316</ref> <ref>PMID:9361025</ref> <ref>PMID:8990018</ref> <ref>PMID:9266356</ref> <ref>PMID:10462600</ref> <ref>PMID:10215408</ref> <ref>PMID:9889017</ref> <ref>PMID:10408774</ref> <ref>PMID:11013450</ref> <ref>PMID:11359213</ref> <ref>PMID:11553052</ref> <ref>PMID:12007221</ref> <ref>PMID:12124992</ref> <ref>PMID:12815602</ref> <ref>PMID:14635102</ref> <ref>PMID:15146473</ref> <ref>PMID:15365998</ref> <ref>PMID:15993874</ref> <ref>PMID:16205833</ref> <ref>PMID:16429402</ref> <ref>PMID:21520339</ref> <ref>PMID:21240075</ref>
== Function ==
[https://www.uniprot.org/uniprot/CBS_HUMAN CBS_HUMAN] Only known pyridoxal phosphate-dependent enzyme that contains heme. Important regulator of hydrogen sulfide, especially in the brain, utilizing cysteine instead of serine to catalyze the formation of hydrogen sulfide. Hydrogen sulfide is a gastratransmitter with signaling and cytoprotective effects such as acting as a neuromodulator in the brain to protect neurons against hypoxic injury (By similarity).
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Cystathionine beta-synthase (CBS) controls the flux of sulfur from methionine to cysteine, a precursor of glutathione, taurine, and H2S. CBS condenses serine and homocysteine to cystathionine with the help of three cofactors, heme, pyridoxal-5'-phosphate, and S-adenosyl-l-methionine. Inherited deficiency of CBS activity causes homocystinuria, the most frequent disorder of sulfur metabolism. We present the structure of the human enzyme, discuss the unique arrangement of the CBS domains in the C-terminal region, and propose how they interact with the catalytic core of the complementary subunit to regulate access to the catalytic site. This arrangement clearly contrasts with other proteins containing the CBS domain including the recent Drosophila melanogaster CBS structure. The absence of large conformational changes and the crystal structure of the partially activated pathogenic D444N mutant suggest that the rotation of CBS motifs and relaxation of loops delineating the entrance to the catalytic site represent the most likely molecular mechanism of CBS activation by S-adenosyl-l-methionine. Moreover, our data suggest how tetramers, the native quaternary structure of the mammalian CBS enzymes, are formed. Because of its central role in transsulfuration, redox status, and H2S biogenesis, CBS represents a very attractive therapeutic target. The availability of the structure will help us understand the pathogenicity of the numerous missense mutations causing inherited homocystinuria and will allow the rational design of compounds modulating CBS activity.


Authors: Ereno, J., Majtan, T., Oyenarte, I., Kraus, J.P., Martinez, L.A.
Structural basis of regulation and oligomerization of human cystathionine beta-synthase, the central enzyme of transsulfuration.,Ereno-Orbea J, Majtan T, Oyenarte I, Kraus JP, Martinez-Cruz LA Proc Natl Acad Sci U S A. 2013 Sep 16. PMID:24043838<ref>PMID:24043838</ref>


Description: Crystal Structure of Human Cystathionine Beta-Synthase
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 4l3v" style="background-color:#fffaf0;"></div>
 
==See Also==
*[[Cystathionine β-synthase 3D structures|Cystathionine β-synthase 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Ereno J]]
[[Category: Kraus JP]]
[[Category: Majtan T]]
[[Category: Martinez LA]]
[[Category: Oyenarte I]]

Latest revision as of 19:10, 20 September 2023

Crystal structure of delta516-525 human cystathionine beta-synthaseCrystal structure of delta516-525 human cystathionine beta-synthase

Structural highlights

4l3v is a 3 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 3.628Å
Ligands:,
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

CBS_HUMAN Defects in CBS are the cause of cystathionine beta-synthase deficiency (CBSD) [MIM:236200. CBSD is an enzymatic deficiency resulting in altered sulfur metabolism and homocystinuria. The clinical features of untreated homocystinuria due to CBS deficiency include myopia, ectopia lentis, mental retardation, skeletal anomalies resembling Marfan syndrome, and thromboembolic events. Light skin and hair can also be present. Biochemical features include increased urinary homocystine and methionine.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35]

Function

CBS_HUMAN Only known pyridoxal phosphate-dependent enzyme that contains heme. Important regulator of hydrogen sulfide, especially in the brain, utilizing cysteine instead of serine to catalyze the formation of hydrogen sulfide. Hydrogen sulfide is a gastratransmitter with signaling and cytoprotective effects such as acting as a neuromodulator in the brain to protect neurons against hypoxic injury (By similarity).

Publication Abstract from PubMed

Cystathionine beta-synthase (CBS) controls the flux of sulfur from methionine to cysteine, a precursor of glutathione, taurine, and H2S. CBS condenses serine and homocysteine to cystathionine with the help of three cofactors, heme, pyridoxal-5'-phosphate, and S-adenosyl-l-methionine. Inherited deficiency of CBS activity causes homocystinuria, the most frequent disorder of sulfur metabolism. We present the structure of the human enzyme, discuss the unique arrangement of the CBS domains in the C-terminal region, and propose how they interact with the catalytic core of the complementary subunit to regulate access to the catalytic site. This arrangement clearly contrasts with other proteins containing the CBS domain including the recent Drosophila melanogaster CBS structure. The absence of large conformational changes and the crystal structure of the partially activated pathogenic D444N mutant suggest that the rotation of CBS motifs and relaxation of loops delineating the entrance to the catalytic site represent the most likely molecular mechanism of CBS activation by S-adenosyl-l-methionine. Moreover, our data suggest how tetramers, the native quaternary structure of the mammalian CBS enzymes, are formed. Because of its central role in transsulfuration, redox status, and H2S biogenesis, CBS represents a very attractive therapeutic target. The availability of the structure will help us understand the pathogenicity of the numerous missense mutations causing inherited homocystinuria and will allow the rational design of compounds modulating CBS activity.

Structural basis of regulation and oligomerization of human cystathionine beta-synthase, the central enzyme of transsulfuration.,Ereno-Orbea J, Majtan T, Oyenarte I, Kraus JP, Martinez-Cruz LA Proc Natl Acad Sci U S A. 2013 Sep 16. PMID:24043838[36]

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

See Also

References

  1. ↑ Kozich V, Kraus JP. Screening for mutations by expressing patient cDNA segments in E. coli: homocystinuria due to cystathionine beta-synthase deficiency. Hum Mutat. 1992;1(2):113-23. PMID:1301198 doi:http://dx.doi.org/10.1002/humu.1380010206
  2. ↑ Kozich V, de Franchis R, Kraus JP. Molecular defect in a patient with pyridoxine-responsive homocystinuria. Hum Mol Genet. 1993 Jun;2(6):815-6. PMID:8353501
  3. ↑ Hu FL, Gu Z, Kozich V, Kraus JP, Ramesh V, Shih VE. Molecular basis of cystathionine beta-synthase deficiency in pyridoxine responsive and nonresponsive homocystinuria. Hum Mol Genet. 1993 Nov;2(11):1857-60. PMID:7506602
  4. ↑ de Franchis R, Kozich V, McInnes RR, Kraus JP. Identical genotypes in siblings with different homocystinuric phenotypes: identification of three mutations in cystathionine beta-synthase using an improved bacterial expression system. Hum Mol Genet. 1994 Jul;3(7):1103-8. PMID:7981678
  5. ↑ Marble M, Geraghty MT, de Franchis R, Kraus JP, Valle D. Characterization of a cystathionine beta-synthase allele with three mutations in cis in a patient with B6 nonresponsive homocystinuria. Hum Mol Genet. 1994 Oct;3(10):1883-6. PMID:7849717
  6. ↑ Kraus JP. Komrower Lecture. Molecular basis of phenotype expression in homocystinuria. J Inherit Metab Dis. 1994;17(4):383-90. PMID:7967489
  7. ↑ Shih VE, Fringer JM, Mandell R, Kraus JP, Berry GT, Heidenreich RA, Korson MS, Levy HL, Ramesh V. A missense mutation (I278T) in the cystathionine beta-synthase gene prevalent in pyridoxine-responsive homocystinuria and associated with mild clinical phenotype. Am J Hum Genet. 1995 Jul;57(1):34-9. PMID:7611293
  8. ↑ Sebastio G, Sperandeo MP, Panico M, de Franchis R, Kraus JP, Andria G. The molecular basis of homocystinuria due to cystathionine beta-synthase deficiency in Italian families, and report of four novel mutations. Am J Hum Genet. 1995 Jun;56(6):1324-33. PMID:7762555
  9. ↑ Kluijtmans LA, Blom HJ, Boers GH, van Oost BA, Trijbels FJ, van den Heuvel LP. Two novel missense mutations in the cystathionine beta-synthase gene in homocystinuric patients. Hum Genet. 1995 Aug;96(2):249-50. PMID:7635485
  10. ↑ Kruger WD, Cox DR. A yeast assay for functional detection of mutations in the human cystathionine beta-synthase gene. Hum Mol Genet. 1995 Jul;4(7):1155-61. PMID:8528202
  11. ↑ Sperandeo MP, Panico M, Pepe A, Candito M, de Franchis R, Kraus JP, Andria G, Sebastio G. Molecular analysis of patients affected by homocystinuria due to cystathionine beta-synthase deficiency: report of a new mutation in exon 8 and a deletion in intron 11. J Inherit Metab Dis. 1995;18(2):211-4. PMID:7564249
  12. ↑ Kluijtmans LA, Boers GH, Stevens EM, Renier WO, Kraus JP, Trijbels FJ, van den Heuvel LP, Blom HJ. Defective cystathionine beta-synthase regulation by S-adenosylmethionine in a partially pyridoxine responsive homocystinuria patient. J Clin Invest. 1996 Jul 15;98(2):285-9. PMID:8755636 doi:10.1172/JCI118791
  13. ↑ Sperandeo MP, Candito M, Sebastio G, Rolland MO, Turc-Carel C, Giudicelli H, Dellamonica P, Andria G. Homocysteine response to methionine challenge in four obligate heterozygotes for homocystinuria and relationship with cystathionine beta-synthase mutations. J Inherit Metab Dis. 1996;19(3):351-6. PMID:8803779
  14. ↑ Dawson PA, Cox AJ, Emmerson BT, Dudman NP, Kraus JP, Gordon RB. Characterisation of five missense mutations in the cystathionine beta-synthase gene from three patients with B6-nonresponsive homocystinuria. Eur J Hum Genet. 1997 Jan-Feb;5(1):15-21. PMID:9156316
  15. ↑ Kim CE, Gallagher PM, Guttormsen AB, Refsum H, Ueland PM, Ose L, Folling I, Whitehead AS, Tsai MY, Kruger WD. Functional modeling of vitamin responsiveness in yeast: a common pyridoxine-responsive cystathionine beta-synthase mutation in homocystinuria. Hum Mol Genet. 1997 Dec;6(13):2213-21. PMID:9361025
  16. ↑ Aral B, Coude M, London J, Aupetit J, Chasse JF, Zabot MT, Chadefaux-Vekemans B, Kamoun P. Two novel mutations (K384E and L539S) in the C-terminal moiety of the cystathionine beta-synthase protein in two French pyridoxine-responsive homocystinuria patients. Hum Mutat. 1997;9(1):81-2. PMID:8990018 doi:<81::AID-HUMU18>3.0.CO;2-L 10.1002/(SICI)1098-1004(1997)9:1<81::AID-HUMU18>3.0.CO;2-L
  17. ↑ Kozich V, Janosik M, Sokolova J, Oliveriusova J, Orendac M, Kraus JP, Elleder D. Analysis of CBS alleles in Czech and Slovak patients with homocystinuria: report on three novel mutations E176K, W409X and 1223 + 37 del99. J Inherit Metab Dis. 1997 Jul;20(3):363-6. PMID:9266356
  18. ↑ Tsai MY, Wong PW, Garg U, Hanson NQ, Schwichtenberg K. Two Novel Mutations in the Cystathionine beta-synthase Gene of Homocystinuric Patients. Mol Diagn. 1997 Jun;2(2):129-133. PMID:10462600 doi:10.1054/MODI00200129
  19. ↑ Gordon RB, Cox AJ, Dawson PA, Emmerson BT, Kraus JP, Dudman NP. Mutational analysis of the cystathionine beta-synthase gene: a splicing mutation, two missense mutations and an insertion in patients with homocystinuria. Mutations in brief no. 120. Online. Hum Mutat. 1998;11(4):332. PMID:10215408 doi:<332::AID-HUMU16>3.0.CO;2-P 10.1002/(SICI)1098-1004(1998)11:4<332::AID-HUMU16>3.0.CO;2-P
  20. ↑ Gallagher PM, Naughten E, Hanson NQ, Schwichtenberg K, Bignell M, Yuan M, Ward P, Yap S, Whitehead AS, Tsai MY. Characterization of mutations in the cystathionine beta-synthase gene in Irish patients with homocystinuria. Mol Genet Metab. 1998 Dec;65(4):298-302. PMID:9889017 doi:10.1006/mgme.1998.2771
  21. ↑ de Franchis R, Kraus E, Kozich V, Sebastio G, Kraus JP. Four novel mutations in the cystathionine beta-synthase gene: effect of a second linked mutation on the severity of the homocystinuric phenotype. Hum Mutat. 1999;13(6):453-7. PMID:10408774 doi:<453::AID-HUMU4>3.0.CO;2-K 10.1002/(SICI)1098-1004(1999)13:6<453::AID-HUMU4>3.0.CO;2-K
  22. ↑ Gat-Yablonski G, Mandel H, Fowler B, Taleb O, Sela BA. Homocystinuria in the Arab population of Israel: identification of two novel mutations using DGGE analysis. Hum Mutat. 2000 Oct;16(4):372. PMID:11013450 doi:<372::AID-HUMU12>3.0.CO;2-J 10.1002/1098-1004(200010)16:4<372::AID-HUMU12>3.0.CO;2-J
  23. ↑ Janosik M, Oliveriusova J, Janosikova B, Sokolova J, Kraus E, Kraus JP, Kozich V. Impaired heme binding and aggregation of mutant cystathionine beta-synthase subunits in homocystinuria. Am J Hum Genet. 2001 Jun;68(6):1506-13. Epub 2001 May 15. PMID:11359213 doi:10.1086/320597
  24. ↑ Castro R, Heil SG, Rivera I, Jakobs C, de Almeida IT, Blom HJ. Molecular genetic analysis of the cystathionine beta-synthase gene in Portuguese homocystinuria patients: three novel mutations. Clin Genet. 2001 Aug;60(2):161-3. PMID:11553052
  25. ↑ Maclean KN, Gaustadnes M, Oliveriusova J, Janosik M, Kraus E, Kozich V, Kery V, Skovby F, Rudiger N, Ingerslev J, Stabler SP, Allen RH, Kraus JP. High homocysteine and thrombosis without connective tissue disorders are associated with a novel class of cystathionine beta-synthase (CBS) mutations. Hum Mutat. 2002 Jun;19(6):641-55. PMID:12007221 doi:10.1002/humu.10089
  26. ↑ Gaustadnes M, Wilcken B, Oliveriusova J, McGill J, Fletcher J, Kraus JP, Wilcken DE. The molecular basis of cystathionine beta-synthase deficiency in Australian patients: genotype-phenotype correlations and response to treatment. Hum Mutat. 2002 Aug;20(2):117-26. PMID:12124992 doi:10.1002/humu.10104
  27. ↑ Urreizti R, Balcells S, Rodes M, Vilarinho L, Baldellou A, Couce ML, Munoz C, Campistol J, Pinto X, Vilaseca MA, Grinberg D. Spectrum of CBS mutations in 16 homocystinuric patients from the Iberian Peninsula: high prevalence of T191M and absence of I278T or G307S. Hum Mutat. 2003 Jul;22(1):103. PMID:12815602 doi:10.1002/humu.9153
  28. ↑ Kruger WD, Wang L, Jhee KH, Singh RH, Elsas LJ 2nd. Cystathionine beta-synthase deficiency in Georgia (USA): correlation of clinical and biochemical phenotype with genotype. Hum Mutat. 2003 Dec;22(6):434-41. PMID:14635102 doi:10.1002/humu.10290
  29. ↑ Orendae M, Pronicka E, Kubalska J, Janosik M, Sokolova J, Linnebank M, Koch HG, Kozich V. Identification and functional analysis of two novel mutations in the CBS gene in Polish patients with homocystinuria. Hum Mutat. 2004 Jun;23(6):631. PMID:15146473 doi:10.1002/humu.9249
  30. ↑ Linnebank M, Janosik M, Kozich V, Pronicka E, Kubalska J, Sokolova J, Linnebank A, Schmidt E, Leyendecker C, Klockgether T, Kraus JP, Koch HG. The cystathionine beta-synthase (CBS) mutation c.1224-2A>C in Central Europe: Vitamin B6 nonresponsiveness and a common ancestral haplotype. Hum Mutat. 2004 Oct;24(4):352-3. PMID:15365998 doi:10.1002/humu.9280
  31. ↑ Porto MP, Galdieri LC, Pereira VG, Vergani N, da Rocha JC, Micheletti C, Martins AM, Perez AB, Almeida VD. Molecular analysis of homocystinuria in Brazilian patients. Clin Chim Acta. 2005 Dec;362(1-2):71-8. Epub 2005 Jul 5. PMID:15993874 doi:10.1016/j.cccn.2005.05.030
  32. ↑ Lee SJ, Lee DH, Yoo HW, Koo SK, Park ES, Park JW, Lim HG, Jung SC. Identification and functional analysis of cystathionine beta-synthase gene mutations in patients with homocystinuria. J Hum Genet. 2005;50(12):648-54. Epub 2005 Oct 5. PMID:16205833 doi:10.1007/s10038-005-0312-2
  33. ↑ Urreizti R, Asteggiano C, Cozar M, Frank N, Vilaseca MA, Grinberg D, Balcells S. Functional assays testing pathogenicity of 14 cystathionine-beta synthase mutations. Hum Mutat. 2006 Feb;27(2):211. PMID:16429402 doi:10.1002/humu.9395
  34. ↑ Cozar M, Urreizti R, Vilarinho L, Grosso C, Dodelson de Kremer R, Asteggiano CG, Dalmau J, Garcia AM, Vilaseca MA, Grinberg D, Balcells S. Identification and functional analyses of CBS alleles in Spanish and Argentinian homocystinuric patients. Hum Mutat. 2011 Jul;32(7):835-42. doi: 10.1002/humu.21514. Epub 2011 Jun 7. PMID:21520339 doi:10.1002/humu.21514
  35. ↑ Kwok JS, Fung SL, Lui GC, Law EL, Chan MH, Leung CB, Tang NL. CBS gene mutations found in a Chinese pyridoxine-responsive homocystinuria patient. Pathology. 2011 Jan;43(1):81-3. doi: 10.1097/PAT.0b013e3283419dbb. PMID:21240075 doi:10.1097/PAT.0b013e3283419dbb
  36. ↑ Ereno-Orbea J, Majtan T, Oyenarte I, Kraus JP, Martinez-Cruz LA. Structural basis of regulation and oligomerization of human cystathionine beta-synthase, the central enzyme of transsulfuration. Proc Natl Acad Sci U S A. 2013 Sep 16. PMID:24043838 doi:10.1073/pnas.1313683110

4l3v, resolution 3.63Å

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