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[[File:Met pathway.gif|thumb|400px|The transsulfuration pathway depicting the conversion of [[homocysteine]] to [[cysteine]] in reactions 5 and 6. The required homocysteine is synthesized from [[methionine]] in reactions 1, 2, and 3.]]
[[File:Met pathway.gif|thumb|400px|The reverse transsulfuration pathway depicting the conversion of [[homocysteine]] to [[cysteine]] in reactions 5 and 6. The required homocysteine is synthesized from [[methionine]] in reactions 1, 2, and 3.]]


The '''transsulfuration pathway''' is a [[metabolic pathway]] involving the interconversion of [[cysteine]] and [[homocysteine]], through the intermediate [[cystathionine]]. In eukaryotes, such as humans, the transsulfuration pathway is critical for creating cysteine from the essential amino acid methionine. Methionine is first converted to homocysteine by demethylation, which is then converted to the amino acid cysteine via the transsulfuration pathway. While methionine is considered an essential amino acid, cysteine becomes an essential amino acid when the transsulfuration pathway is defective.
The '''transsulfuration pathway''' is a [[metabolic pathway]] involving the interconversion of [[cysteine]] and [[homocysteine]], through the intermediate [[cystathionine]].
This is in contrast to the direct sulfurylation pathways for the synthesis of cysteine or homocysteine via the replacement of the acetyl/succinyl group with free sulfide (via the ''cysK'' or ''cysM'' -encoded cysteine synthase<ref>{{cite doi|10.1074/jbc.R400001200}}</ref> and the ''metZ'' or ''metY'' -encoded homocysteine synthase<ref>{{cite pmid|11844756}}</ref>, respectively).


Two transsulfurylation pathway are known, the forward pathway and the reverse.
⚫
In organisms that synthesize cysteine in [[sulfur assimilation]] such as bacteria and yeast, the transsulfuration pathway works in reverse. The production of homocysteine through transsulfuration allows the conversion of this intermediate to [[methionine]], through a methylation reaction carried out by [[5-Methyltetrahydrofolate-homocysteine methyltransferase|methionine synthase]].
The forward pathway is present is several bacteria for example in ''Escherichia coli''<ref>{{cite pmid|21435402}}</ref> and ''Bacillus subtilis''<ref>{{cite pmid|11832514}}</ref> and involves the transfer of the thiol group from cysteine to homocysteine (methionine precursor with the S-methyl group), thanks to the γ-replacement of the acetyl or succinyl group of a homoserine ester with cysteine via its thiol group to form cystathionine (catalysed by [[Cystathionine gamma-synthase|cystathionine γ-synthase]], which is encoded by ''metB'' in ''E. coli'' and ''metI'' in ''B. subtilis''. Cystathionine is then cleaved by means of the β-elimination of the homocysteine portion of the molecule leaving behind an unstable imino acid, which is attacked by water to form pyruvate and ammonia (catalysed by the metC-encoded [[Cystathionine beta-lyase|cystathionine β-lyase]]<ref>{{cite pmid|8831789}}</ref>).
⚫
The production of homocysteine through transsulfuration allows the conversion of this intermediate to [[methionine]], through a methylation reaction carried out by [[5-Methyltetrahydrofolate-homocysteine methyltransferase|methionine synthase]].

The reverse pathway is present in several organisms, including humans, and involves the transfer of the thiol group from homocysteine to cysteine via a similar mechanism. In ''Klebsiella pneumoniae'' the [[cystathionine beta-synthase|cystathionine β-synthase]] is encoded by ''mtcB'', while the [[Cystathionine gamma-lyase|γ-lyase]] is encoded by ''mtcC''.<ref>{{cite pmid|16885444}}</ref>
Humans are auxotrophic for methionine, hence it is called an "essential amino acid" by nutrionalists, but are not for cysteine due to the reverse trans-sulfurylation pathway. Mutations in this pathway lead to a disease known as [[homocystinuria]].<!--The symptoms of this disease are not due to cysteine auxotrophy as stated here before, but due to homocysteine accumulation-->

==PLP==
{{main|Cys/Met metabolism PLP-dependent enzyme family}} <!--THE FOLLOWING IS A COPY PASTE FROM THIS!!!-->
All four transsulfuration enzymes are [[PLP|PLP enzymes]] and all bar Cystathionine γ-synthase are members of the Cys/Met metabolism PLP-dependent enzyme family (type I PLP enzymes).

There are five different structurally related types of PLP enzymes in this family. Members of this family belong to the type I and are:<ref name="Aitken structure">{{cite doi|10.1016/j.bbapap.2011.03.006}}</ref>
* in the transsulfurylation route for methionine biosynthesis:
** Cystathionine γ-synthase (''metB'') which joins an activated homoserine ether (acetyl or succinyl) with cysteine to form cystathionine
** Cystathionine β-lyase (''metC'') which splits cystathionine into homocysteine and a deaminated alanine (pyruvate and ammonia)
* in the direct sulfurylation pathway for methionine biosynthesis:
** O-acetyl homoserine sulfhydrylase (''metY'') which adds a thiol group to an activated homoserine ether
** O-succinylhomoserine sulfhydrylase (''metZ'') which adds a thiol group to an activated homoserine ether
* in the reverse transsulfurylation pathway for cysteine biosynthesis:
** Cystathionine γ-lyase (no common gene name) which joins an activated serine ether (acetyl or succinyl) with homocysteine to form cystathionine
** Not Cystathionine β-synthase which is a PLP enzyme type II
* cysteine biosynthesis from serine:
** O-acetyl serine sulfhydrylase (''cysK'' or ''cysM'') which adds a thiol group to an activated serine ether
* methionine degradation:
* Methionine gamma-lyase (''mdeA'') which breaks down methionine at the thioether and amine bounds

Note: MetC, metB, metZ are closely related and have fuzzy boundaries so fall under the same NCBI orthologue cluster (COG0626).


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Revision as of 01:42, 12 August 2013

The reverse transsulfuration pathway depicting the conversion of homocysteine to cysteine in reactions 5 and 6. The required homocysteine is synthesized from methionine in reactions 1, 2, and 3.

The transsulfuration pathway is a metabolic pathway involving the interconversion of cysteine and homocysteine, through the intermediate cystathionine. This is in contrast to the direct sulfurylation pathways for the synthesis of cysteine or homocysteine via the replacement of the acetyl/succinyl group with free sulfide (via the cysK or cysM -encoded cysteine synthase[1] and the metZ or metY -encoded homocysteine synthase[2], respectively).

Two transsulfurylation pathway are known, the forward pathway and the reverse. The forward pathway is present is several bacteria for example in Escherichia coli[3] and Bacillus subtilis[4] and involves the transfer of the thiol group from cysteine to homocysteine (methionine precursor with the S-methyl group), thanks to the γ-replacement of the acetyl or succinyl group of a homoserine ester with cysteine via its thiol group to form cystathionine (catalysed by cystathionine γ-synthase, which is encoded by metB in E. coli and metI in B. subtilis. Cystathionine is then cleaved by means of the β-elimination of the homocysteine portion of the molecule leaving behind an unstable imino acid, which is attacked by water to form pyruvate and ammonia (catalysed by the metC-encoded cystathionine β-lyase[5]). The production of homocysteine through transsulfuration allows the conversion of this intermediate to methionine, through a methylation reaction carried out by methionine synthase.

The reverse pathway is present in several organisms, including humans, and involves the transfer of the thiol group from homocysteine to cysteine via a similar mechanism. In Klebsiella pneumoniae the cystathionine β-synthase is encoded by mtcB, while the γ-lyase is encoded by mtcC.[6] Humans are auxotrophic for methionine, hence it is called an "essential amino acid" by nutrionalists, but are not for cysteine due to the reverse trans-sulfurylation pathway. Mutations in this pathway lead to a disease known as homocystinuria.

PLP

Main article: Cys/Met metabolism PLP-dependent enzyme family

All four transsulfuration enzymes are PLP enzymes and all bar Cystathionine γ-synthase are members of the Cys/Met metabolism PLP-dependent enzyme family (type I PLP enzymes).

There are five different structurally related types of PLP enzymes in this family. Members of this family belong to the type I and are:[7]

  • in the transsulfurylation route for methionine biosynthesis:
    • Cystathionine γ-synthase (metB) which joins an activated homoserine ether (acetyl or succinyl) with cysteine to form cystathionine
    • Cystathionine β-lyase (metC) which splits cystathionine into homocysteine and a deaminated alanine (pyruvate and ammonia)
  • in the direct sulfurylation pathway for methionine biosynthesis:
    • O-acetyl homoserine sulfhydrylase (metY) which adds a thiol group to an activated homoserine ether
    • O-succinylhomoserine sulfhydrylase (metZ) which adds a thiol group to an activated homoserine ether
  • in the reverse transsulfurylation pathway for cysteine biosynthesis:
    • Cystathionine γ-lyase (no common gene name) which joins an activated serine ether (acetyl or succinyl) with homocysteine to form cystathionine
    • Not Cystathionine β-synthase which is a PLP enzyme type II
  • cysteine biosynthesis from serine:
    • O-acetyl serine sulfhydrylase (cysK or cysM) which adds a thiol group to an activated serine ether
  • methionine degradation:
  • Methionine gamma-lyase (mdeA) which breaks down methionine at the thioether and amine bounds

Note: MetC, metB, metZ are closely related and have fuzzy boundaries so fall under the same NCBI orthologue cluster (COG0626).

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  1. ^ Attention: This template ({{cite doi}}) is deprecated. To cite the publication identified by doi:10.1074/jbc.R400001200, please use {{cite journal}} (if it was published in a bona fide academic journal, otherwise {{cite report}} with |doi=10.1074/jbc.R400001200 instead.
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