Cystathionine β-synthase - Revision history

Michal Harel at 09:58, 3 July 2022

2022-07-03T09:58:31Z

←Older revision		Revision as of 09:58, 3 July 2022
Line 81:		Line 81:
	==3D structures of Cystathionine β-synthase==		==3D structures of Cystathionine β-synthase==

-	[[Cystathionine β-synthase]]	+	[[Cystathionine β-synthase 3D structures]]
		+
	</StructureSection>		</StructureSection>

Michal Harel at 09:57, 3 July 2022

2022-07-03T09:57:03Z

←Older revision		Revision as of 09:57, 3 July 2022
Line 78:		Line 78:
	The first one has centered on the relationship between homocysteine and oxidative stress. Homocysteine itself has been shown to cause increased oxidative stress on cells, both through direct effects (e.g., the production of hydrogen peroxide by oxidation of homocysteine to homocystine) and indirect effects (e.g., reduction of glutathione peroxidase). In addition, it is estimated that as much as 50% of the cellular antioxidant glutathione is produced from homocysteine by conversion through the transsulfuration pathway.		The first one has centered on the relationship between homocysteine and oxidative stress. Homocysteine itself has been shown to cause increased oxidative stress on cells, both through direct effects (e.g., the production of hydrogen peroxide by oxidation of homocysteine to homocystine) and indirect effects (e.g., reduction of glutathione peroxidase). In addition, it is estimated that as much as 50% of the cellular antioxidant glutathione is produced from homocysteine by conversion through the transsulfuration pathway.
	A second popular hypothesis suggests that eHcy affects the control of biologically important methylation reactions by causing a build-up of S-adenosyl-L-homocysteine (AdoHcy) which is a competitive inhibitor of S-adenosyl-L-methionine (AdoMet) binding for methyltransferase enzymes. As methyltransferases are involved in a variety of important biological processes, inhibition of this class of enzymes could have extremely diverse effects on the organism.<ref>PMID:15890029</ref>		A second popular hypothesis suggests that eHcy affects the control of biologically important methylation reactions by causing a build-up of S-adenosyl-L-homocysteine (AdoHcy) which is a competitive inhibitor of S-adenosyl-L-methionine (AdoMet) binding for methyltransferase enzymes. As methyltransferases are involved in a variety of important biological processes, inhibition of this class of enzymes could have extremely diverse effects on the organism.<ref>PMID:15890029</ref>
-	</StructureSection>

	==3D structures of Cystathionine β-synthase==		==3D structures of Cystathionine β-synthase==

-	~~Updated on {{REVISIONDAY2}}-{{MONTHNAME\|{{REVISIONMONTH}}}}-{{REVISIONYEAR}}~~	+	[[Cystathionine β-synthase]]
-		+	</StructureSection>
-	[[~~4l3v]], [[4coo]] – hCBS + PLP – human<br />~~	+
-	~~[[5mms]], [[4l0d]], [[4l28]], [[4l27]] – hCBS (mutant) + PLP <br />~~	+
-	~~[[1jbq]] – hCBS 1~~-~~412 (mutant) + PLP <br />~~	+
-	~~[[1m54~~]] ~~– hCBS 44-406 (mutant) + PLP <br />~~	+
-	~~[[4pcu]] – hCBS + PLP + SAM~~<br />	+
-	~~[[4uuu]] – hCBS regulatory domain 406-547 + SAM<br />~~	+
-	~~[[3pc2]] – DmCBS + PLP – ''Drosophila melanogaster''<br />~~	+
-	~~[[3pc3]] – DmCBS + PLP + aminoacrylate<br />~~	+
-	~~[[3pc4]] – DmCBS + PLP + Ser<br />~~	+
-	~~[[5ohx]] – CBS + PLP – bee<br />~~	+
-	~~[[6c2h]] – yCBS catalytic domain 1-353 + PLP – yeast<br />~~	+
-	~~[[6c2q]] – yCBS catalytic domain + PLP-Ser<br />~~	+
-	~~[[6c2z]] – yCBS catalytic domain + PLP-aminoacrylate<br />~~	+
-	~~[[6c4p]] – yCBS catalytic domain + PMP<br />~~	+
-	~~[[5b1h]] – LpCBS + PLP derivative – ''Lactobacillus plantarum''<br />~~	+
-	~~[[5b1i]] – LpCBS (mutant) + Met derivative<br />~~	+
-	~~[[5xw3]] – CBS – ''Bacillus anthracis''<br />~~	+
-	~~[[4ofx]] – CBS – ''Coxiella burnetii''<br />~~	+
-	~~[[6ahi]] – CBS + PLP derivative + Met – ''Helicobacter pylori''<br />~~	+
-	~~[[6r2q]] – CBS + protein + decamere C-type cytochrome – ''Shewanella baltica''<br />~~	+
-		+

	== Credits ==		== Credits ==

Michal Harel at 08:02, 9 July 2020

2020-07-09T08:02:44Z

←Older revision		Revision as of 08:02, 9 July 2020
Line 101:		Line 101:
	[[5b1i]] – LpCBS (mutant) + Met derivative<br />		[[5b1i]] – LpCBS (mutant) + Met derivative<br />
	[[5xw3]] – CBS – ''Bacillus anthracis''<br />		[[5xw3]] – CBS – ''Bacillus anthracis''<br />
		+	[[4ofx]] – CBS – ''Coxiella burnetii''<br />
	[[6ahi]] – CBS + PLP derivative + Met – ''Helicobacter pylori''<br />		[[6ahi]] – CBS + PLP derivative + Met – ''Helicobacter pylori''<br />
		+	[[6r2q]] – CBS + protein + decamere C-type cytochrome – ''Shewanella baltica''<br />
		+

	== Credits ==		== Credits ==

Michal Harel at 07:54, 9 January 2020

2020-01-09T07:54:51Z

←Older revision		Revision as of 07:54, 9 January 2020
Line 1:		Line 1:
	==3D Structure of Human Cystathionine β-synthase (4coo)==		==3D Structure of Human Cystathionine β-synthase (4coo)==
	<StructureSection load='4coo' size='340' side='right' caption='Human Cystathionine β-synthase' scene=''>		<StructureSection load='4coo' size='340' side='right' caption='Human Cystathionine β-synthase' scene=''>
-	Cystathionine β-synthase (CBS; EC 4.2.1.22) is a unique pyridoxal 5’-phosphate (PLP) enzyme which plays a crucial role in the transsulfuration metabolic pathway of sulfur-containing amino acid, L-homocysteine.	+	'''Cystathionine β-synthase''' (CBS; EC 4.2.1.22) is a unique pyridoxal 5’-phosphate (PLP) enzyme which plays a crucial role in the transsulfuration metabolic pathway of sulfur-containing amino acid, L-homocysteine.
	PLP enzymes are divided into four families on the basis of similarities in three dimensional structure, sequence, secondary structure, and hydrophobicity profiles. CBS is a member of the β family or Fold type II, which also contains O-acetylserine sulfhydrylase (OASS) and O-acetyl-L-serine(thiol)lyase (OASTL)<ref>PMID:11483494</ref>.		PLP enzymes are divided into four families on the basis of similarities in three dimensional structure, sequence, secondary structure, and hydrophobicity profiles. CBS is a member of the β family or Fold type II, which also contains O-acetylserine sulfhydrylase (OASS) and O-acetyl-L-serine(thiol)lyase (OASTL)<ref>PMID:11483494</ref>.

Michal Harel at 07:53, 9 January 2020

2020-01-09T07:53:58Z

←Older revision		Revision as of 07:53, 9 January 2020
Line 79:		Line 79:
	A second popular hypothesis suggests that eHcy affects the control of biologically important methylation reactions by causing a build-up of S-adenosyl-L-homocysteine (AdoHcy) which is a competitive inhibitor of S-adenosyl-L-methionine (AdoMet) binding for methyltransferase enzymes. As methyltransferases are involved in a variety of important biological processes, inhibition of this class of enzymes could have extremely diverse effects on the organism.<ref>PMID:15890029</ref>		A second popular hypothesis suggests that eHcy affects the control of biologically important methylation reactions by causing a build-up of S-adenosyl-L-homocysteine (AdoHcy) which is a competitive inhibitor of S-adenosyl-L-methionine (AdoMet) binding for methyltransferase enzymes. As methyltransferases are involved in a variety of important biological processes, inhibition of this class of enzymes could have extremely diverse effects on the organism.<ref>PMID:15890029</ref>
	</StructureSection>		</StructureSection>
		+
		+	==3D structures of Cystathionine β-synthase==
		+
		+	Updated on {{REVISIONDAY2}}-{{MONTHNAME\|{{REVISIONMONTH}}}}-{{REVISIONYEAR}}
		+
		+	[[4l3v]], [[4coo]] – hCBS + PLP – human<br />
		+	[[5mms]], [[4l0d]], [[4l28]], [[4l27]] – hCBS (mutant) + PLP <br />
		+	[[1jbq]] – hCBS 1-412 (mutant) + PLP <br />
		+	[[1m54]] – hCBS 44-406 (mutant) + PLP <br />
		+	[[4pcu]] – hCBS + PLP + SAM<br />
		+	[[4uuu]] – hCBS regulatory domain 406-547 + SAM<br />
		+	[[3pc2]] – DmCBS + PLP – ''Drosophila melanogaster''<br />
		+	[[3pc3]] – DmCBS + PLP + aminoacrylate<br />
		+	[[3pc4]] – DmCBS + PLP + Ser<br />
		+	[[5ohx]] – CBS + PLP – bee<br />
		+	[[6c2h]] – yCBS catalytic domain 1-353 + PLP – yeast<br />
		+	[[6c2q]] – yCBS catalytic domain + PLP-Ser<br />
		+	[[6c2z]] – yCBS catalytic domain + PLP-aminoacrylate<br />
		+	[[6c4p]] – yCBS catalytic domain + PMP<br />
		+	[[5b1h]] – LpCBS + PLP derivative – ''Lactobacillus plantarum''<br />
		+	[[5b1i]] – LpCBS (mutant) + Met derivative<br />
		+	[[5xw3]] – CBS – ''Bacillus anthracis''<br />
		+	[[6ahi]] – CBS + PLP derivative + Met – ''Helicobacter pylori''<br />
		+
	== Credits ==		== Credits ==
	Article created as an [https://is.cuni.cz/studium/predmety/index.php?id=b0728408dfab8c4e0250521ab9988dd8&tid=&do=predmet&kod=MB151P117&skr=2018 Structural biology of the cell] assignment at the Faculty of Science, Charles University, Prague, Czech Republic.		Article created as an [https://is.cuni.cz/studium/predmety/index.php?id=b0728408dfab8c4e0250521ab9988dd8&tid=&do=predmet&kod=MB151P117&skr=2018 Structural biology of the cell] assignment at the Faculty of Science, Charles University, Prague, Czech Republic.
Line 85:		Line 109:
	== References ==		== References ==
	<references/>		<references/>
		+
		+	[[Category:Topic Page]]

Jan Hamalcik at 22:09, 22 May 2019

2019-05-22T22:09:36Z

←Older revision		Revision as of 22:09, 22 May 2019
Line 53:		Line 53:
	'''Mutations in the heme-binding site'''		'''Mutations in the heme-binding site'''
	Mutations in this part of the enzyme reduces the ability to bind heme and affects proper folding of CBS.		Mutations in this part of the enzyme reduces the ability to bind heme and affects proper folding of CBS.
		+	[[Image:Stereo picture of the CBS' heme binding pocket.png\|600px\|left Stereo picture of the heme binding pocket. Atoms are colour-coded according to atom type (grey: carbon, red: oxygen, blue: nitrogen, green: phosphorus); mutated residues are labelled and their carbon atoms are coloured in magenta.]]<ref>PMID:12686134</ref>

	'''Mutations in the dimer interface'''		'''Mutations in the dimer interface'''

Jan Hamalcik at 22:05, 22 May 2019

2019-05-22T22:05:11Z

←Older revision		Revision as of 22:05, 22 May 2019
Line 49:		Line 49:
	'''Mutations in active site'''		'''Mutations in active site'''
	The active site is accessible only via a narrow channel. Four of the six known point mutations in the active site involve glycine residues: G148R, G305R, G307S and G259S. The residue G259 separates the active site from the heme-binding pocket. The residue G307 lines the entry to the active site cleft and the orientation of G307 do not allow accommodating of the side chain of a serine residue which causes incorporation of the side chain and conformation change in the loop.<ref>PMID:20506325</ref> As the second substrate homocysteine probably binds here the mutation could inhibit binding of homocysteine.		The active site is accessible only via a narrow channel. Four of the six known point mutations in the active site involve glycine residues: G148R, G305R, G307S and G259S. The residue G259 separates the active site from the heme-binding pocket. The residue G307 lines the entry to the active site cleft and the orientation of G307 do not allow accommodating of the side chain of a serine residue which causes incorporation of the side chain and conformation change in the loop.<ref>PMID:20506325</ref> As the second substrate homocysteine probably binds here the mutation could inhibit binding of homocysteine.
		+	[[Image:Stereo picture of the CBS' active site.png\|600px\|left Stereo picture of the active site. Atoms are colour-coded according to atom type (grey: carbon, red: oxygen, blue: nitrogen, green: phosphorus); mutated residues are labelled and their carbon atoms are coloured in magenta. Hydrogen bonds between the PLP cofactor and the surrounding residues are shown as black dotted lines.]]<ref>PMID:12686134</ref>

	'''Mutations in the heme-binding site'''		'''Mutations in the heme-binding site'''

Jan Hamalcik at 21:55, 22 May 2019

2019-05-22T21:55:51Z

←Older revision		Revision as of 21:55, 22 May 2019
Line 45:		Line 45:

	== Mutations in CBS gene ==		== Mutations in CBS gene ==
-	There are more than 100 reported mutations in CBS gene from patients with homocystinuria most of which are missense. Among most frequent mutations is I278T (c.833T>C) in C-terminal domain found in about 25 % of all homocystinuric alleles, and G307S (c.919G>A) located in active site.<ref>PMID:10338090</ref>	+	There are more than 100 reported mutations in CBS gene from patients with homocystinuria most of which are missense. Among most frequent mutations is I278T (c.833T>C) in C-terminal domain found in about 25 % of all homocystinuric alleles, and G307S (c.919G>A) located in active site.<ref>PMID:12686134</ref><ref>PMID:10338090</ref>

	'''Mutations in active site'''		'''Mutations in active site'''

Jan Hamalcik at 21:53, 22 May 2019

2019-05-22T21:53:51Z

←Older revision		Revision as of 21:53, 22 May 2019
Line 76:		Line 76:
	The first one has centered on the relationship between homocysteine and oxidative stress. Homocysteine itself has been shown to cause increased oxidative stress on cells, both through direct effects (e.g., the production of hydrogen peroxide by oxidation of homocysteine to homocystine) and indirect effects (e.g., reduction of glutathione peroxidase). In addition, it is estimated that as much as 50% of the cellular antioxidant glutathione is produced from homocysteine by conversion through the transsulfuration pathway.		The first one has centered on the relationship between homocysteine and oxidative stress. Homocysteine itself has been shown to cause increased oxidative stress on cells, both through direct effects (e.g., the production of hydrogen peroxide by oxidation of homocysteine to homocystine) and indirect effects (e.g., reduction of glutathione peroxidase). In addition, it is estimated that as much as 50% of the cellular antioxidant glutathione is produced from homocysteine by conversion through the transsulfuration pathway.
	A second popular hypothesis suggests that eHcy affects the control of biologically important methylation reactions by causing a build-up of S-adenosyl-L-homocysteine (AdoHcy) which is a competitive inhibitor of S-adenosyl-L-methionine (AdoMet) binding for methyltransferase enzymes. As methyltransferases are involved in a variety of important biological processes, inhibition of this class of enzymes could have extremely diverse effects on the organism.<ref>PMID:15890029</ref>		A second popular hypothesis suggests that eHcy affects the control of biologically important methylation reactions by causing a build-up of S-adenosyl-L-homocysteine (AdoHcy) which is a competitive inhibitor of S-adenosyl-L-methionine (AdoMet) binding for methyltransferase enzymes. As methyltransferases are involved in a variety of important biological processes, inhibition of this class of enzymes could have extremely diverse effects on the organism.<ref>PMID:15890029</ref>
-
-	== Molecular dynamic simulation ==
-	For this project we also include animated gif files of our very own molecular dynamic simulation of the solvated and ionized CBS. Movement of the enzyme has been computed by CHARMM in MetaCentrum VO. Input has been prepared in VMD from 4coo PDB file.
-
-	Animation should be visible upon clicking on the images.
-	[[Image:CBS Lines.gif]]
-	[[Image:CBS NewCartoon.gif]]
	</StructureSection>		</StructureSection>
	== Credits ==		== Credits ==

Jan Hamalcik at 21:50, 22 May 2019

2019-05-22T21:50:50Z

←Older revision		Revision as of 21:50, 22 May 2019
Line 42:		Line 42:
	The type of reaction mechanisms used by the CBS is known as a double displacement or ping-pong mechanism. The rate determining step in the reaction is hydrolysis of the external aldimine of cystathionine.<ref>PMID:15890029</ref>		The type of reaction mechanisms used by the CBS is known as a double displacement or ping-pong mechanism. The rate determining step in the reaction is hydrolysis of the external aldimine of cystathionine.<ref>PMID:15890029</ref>
	[[Image:Reactions catalyzed by CBS.png\|600px\|left Reactions catalyzed by CBS. (A) Canonical reaction of CBS. (B) CBS reactions that generate or utilize H2S.]]		[[Image:Reactions catalyzed by CBS.png\|600px\|left Reactions catalyzed by CBS. (A) Canonical reaction of CBS. (B) CBS reactions that generate or utilize H2S.]]
-	[[Image:Proposed enzymatic mechanism for the CBS.png\|600px\|left Proposed enzymatic mechanism for the CBS reaction with absorption maxima. Possible quinonoid intermediates between E-serine (E-PLP-L-ser) and E-aminoacrylate (E-PLPaa) or between E-aminoacrylate and E-cystathionine are not shown. The growing consensus among those working on fold type-II PLP-dependent enzymes is that the ring nitrogen does not undergo protonation during the catalytic cycle in these enzymes. However, at pH 6.5 the expectation is that the ring nitrogen is protonated as shown.]]	+	[[Image:Proposed enzymatic mechanism for the CBS.png\|600px\|left Proposed enzymatic mechanism for the CBS reaction with absorption maxima. Possible quinonoid intermediates between E-serine (E-PLP-L-ser) and E-aminoacrylate (E-PLPaa) or between E-aminoacrylate and E-cystathionine are not shown. The growing consensus among those working on fold type-II PLP-dependent enzymes is that the ring nitrogen does not undergo protonation during the catalytic cycle in these enzymes. However, at pH 6.5 the expectation is that the ring nitrogen is protonated as shown.]]<ref>PMID: 29630349</ref>

	== Mutations in CBS gene ==		== Mutations in CBS gene ==