Editing Methionine (section)

== Biosynthesis ==
[[File:Met biosynthesis.svg|thumb|550px|Methionine biosynthesis]]
As an essential amino acid, methionine is not synthesized [[De novo synthesis|''de novo'']] in humans and other animals, which must ingest methionine or methionine-containing proteins.  In plants and microorganisms, methionine biosynthesis belongs to the [[aspartate]] family, along with threonine and [[lysine]] (via [[diaminopimelate]], but not via [[Alpha-Aminoadipic acid|α-aminoadipate]]). The main backbone is derived from [[aspartic acid]], while the sulfur may come from [[cysteine]], [[methanethiol]], or [[hydrogen sulfide]].<ref name=review/>
* First, aspartic acid is converted via β-aspartyl semialdehyde into [[homoserine]] by two reduction steps of the terminal carboxyl group (homoserine has therefore a γ-hydroxyl, hence the [[homologous series|homo-]] series). The intermediate aspartate semialdehyde is the branching point with the lysine biosynthetic pathway, where it is instead [[Aldol condensation|condensed]] with pyruvate. Homoserine is the branching point with the threonine pathway, where instead it is isomerised after activating the terminal hydroxyl with phosphate (also used for methionine biosynthesis in plants).<ref name=review/>
* Homoserine is then activated with a phosphate, succinyl or an acetyl group on the hydroxyl.
** In plants and possibly in some bacteria,<ref name=review/> phosphate is used. This step is shared with threonine biosynthesis.<ref name=review/>
** In most organisms, an acetyl group is used to activate the homoserine. This can be catalysed in bacteria by an enzyme encoded by ''metX'' or ''metA'' (not homologues).<ref name=review/>
** In [[Enterobacteriaceae|enterobacteria]] and a limited number of other organisms, succinate is used. The enzyme that catalyses the reaction is MetA and the specificity for acetyl-CoA and succinyl-CoA is dictated by a single residue.<ref name=review/> The physiological basis for the preference of acetyl-CoA or succinyl-CoA is unknown, but such alternative routes are present in some other pathways (''e.g.'' lysine biosynthesis and arginine biosynthesis).
* The hydroxyl activating group is then replaced with cysteine, methanethiol, or hydrogen sulfide. A replacement reaction is technically a γ-[[Elimination reaction|elimination]] followed by a variant of a [[Michael addition]]. All the enzymes involved are homologues and members of the [[Cys/Met metabolism PLP-dependent enzyme family]], which is a subset of the PLP-dependent fold type I clade. They utilise the cofactor PLP ([[pyridoxal phosphate]]), which functions by stabilising carbanion intermediates.<ref name=review/>
** If it reacts with cysteine, it produces [[cystathionine]], which is cleaved to yield [[homocysteine]]. The enzymes involved are [[cystathionine-γ-synthase]] (encoded by ''metB'' in bacteria) and [[cystathionine-β-lyase]] (''metC''). Cystathionine is bound differently in the two enzymes allowing β or γ reactions to occur.<ref name=review/>
** If it reacts with free hydrogen sulfide, it produces homocysteine. This is catalysed by [[O-acetylhomoserine aminocarboxypropyltransferase|''O''-acetylhomoserine aminocarboxypropyltransferase]] (formerly known as ''O''-acetylhomoserine (thiol)-lyase. It is encoded by either ''metY'' or ''metZ'' in bacteria.<ref name=review/>
** If it reacts with  methanethiol, it produces methionine directly. Methanethiol is a byproduct of catabolic pathway of certain compounds, therefore this route is more uncommon.<ref name=review/>
* If homocysteine is produced, the thiol group is methylated, yielding methionine. Two [[methionine synthase]]s are known; one is [[cobalamin]] (vitamin B<sub>12</sub>) dependent and one is independent.<ref name=review/>

The pathway using cysteine is called the "[[transsulfuration pathway]]", while the pathway using hydrogen sulfide (or methanethiol) is called "direct-sulfurylation pathway".

Cysteine is similarly produced, namely it can be made from an activated serine and either from homocysteine ("reverse transsulfurylation route") or from hydrogen sulfide ("direct sulfurylation route"); the activated serine is generally ''O''-acetylserine (via CysK or CysM in ''E. coli''), but in ''[[Aeropyrum pernix]]'' and some other archaea ''O''-phosphoserine is used.<ref>{{Cite journal |vauthors=Mino K, Ishikawa K |date=September 2003 |title=A novel ''O''-phospho-<small>L</small>-serine sulfhydrylation reaction catalyzed by ''O''-acetylserine sulfhydrylase from ''Aeropyrum pernix'' K1 |journal=FEBS Letters |volume=551 |issue=1–3 |pages=133–138 |doi=10.1016/S0014-5793(03)00913-X |pmid=12965218|s2cid=28360765 |doi-access=free }}</ref> CysK and CysM are homologues, but belong to the PLP fold type III clade.{{cn|date=October 2024}}

===Transsulfurylation pathway===
{{Main|Transsulfuration pathway}}
Enzymes involved in the ''E. coli'' transsulfurylation route of methionine biosynthesis:{{cn|date=October 2024}}
# [[Aspartokinase]]
# [[Aspartate-semialdehyde dehydrogenase]]
# [[Homoserine dehydrogenase]]
# [[Homoserine O-transsuccinylase|Homoserine ''O''-transsuccinylase]]
# [[Cystathionine-γ-synthase]]
# [[Cystathionine-β-lyase]]
# [[Methionine synthase]] (in mammals, this step is performed by [[homocysteine methyltransferase]] or [[betaine—homocysteine S-methyltransferase|betaine—homocysteine ''S''-methyltransferase]].)