L-lysine biosynthesis via alpha-aminoadipate

De novo biosynthesis of L-lysine from 2-oxoglutarate and acetyl-CoA through the C6 intermediate L-2-aminoadipate (alpha-aminoadipate, AAA). This route is chemically unrelated to the diaminopimelate pathway of most bacteria and plants. Its first half extends the carbon chain by one methylene unit through reactions homologous to the citrate-to-2-oxoglutarate segment of the tricarboxylic acid cycle and to leucine biosynthesis: homocitrate synthase condenses acetyl-CoA with 2-oxoglutarate, homocitrate is isomerised to homoisocitrate in two aconitase-family steps (homocitrate dehydration to cis-homoaconitate, then hydration to homoisocitrate), homoisocitrate dehydrogenase oxidatively decarboxylates homoisocitrate to 2-oxoadipate, and a transaminase produces L-2-aminoadipate. The second half diverges by lineage. In fungi, a large phosphopantetheinylated alpha-aminoadipate reductase reduces AAA to its 6-semialdehyde, which is reductively condensed with L-glutamate to saccharopine and then cleaved to L-lysine and 2-oxoglutarate. In Thermus and in Sulfolobus and other archaea, AAA is instead ligated to the C-terminal glutamate of the small carrier protein LysW and converted to lysine by ArgB/C/D-like enzymes before a hydrolase releases free lysine. In fungi the early steps are split between compartments, with homocitrate isomerisation and homoisocitrate oxidation in the mitochondrial matrix and the final steps in the cytosol and peroxisome.

Boundary: begins at homocitrate synthase (the committed, lysine-inhibited step) and ends with free L-lysine. 2-oxoglutarate and acetyl-CoA supply (TCA cycle; the S. pombe GO-CAM includes idh1/idh2), regulation (Lys14, Gcn4, HCS feedback inhibition), lysine uptake and mitochondrial import, and lysyl-tRNA charging are outside the module. The crosswalk rationale is followed: the homocitrate-to-AAA half is shared by fungi and LysW-type prokaryotes and the AAA-to-lysine half is a two-way variant set. YeastCyc corrections: (1) the homocitrate -> cis-homoaconitate reaction (RXN3O-1983) is catalysed by the aconitase paralog ACO2, not LYS4 (PMID:23106124); LYS4 only hydrates cis-homoaconitate. (2) ARO8 (the cytosolic AAA transaminase) is missing from the pathway gene list, although the SGD GO-CAM conversion includes it. (3) LYS5, required to activate LYS2, is missing. (4) ODC1/ODC2 export of 2-oxoadipate from mitochondria is not represented. Compartments: YeastCyc and its GO-CAM place every step in the cytosol, but ACO2, LYS4 and LYS12 are mitochondrial, LYS1 is peroxisomal and HCS has been found in the nucleus in S. cerevisiae. GO-CAM disagreements: YeastPathways_LYSINE-AMINOAD-PWY-2 assigns both isomerisation half-reactions to LYS4 (GO:0004409) and puts all activities in cytosol. The PomBase model 667dfe8d00001131 has no homocitrate dehydratase (aco2, SPBP4H10.15) activity; its lys2 homoaconitase activity takes homocitrate directly as input. It also places the AAA transaminase (unidentified gene product) in the mitochondrial matrix, followed by L-2-aminoadipate export, whereas in S. cerevisiae the transaminase (Aro8) is cytosolic and 2-oxoadipate is exported by Odc1/Odc2. The PomBase model places lys12 in the mitochondrial matrix; UniProt reports a cytoplasmic localisation for S. pombe lys12 from a global GFP screen. Ontology gaps (no current GO MF): homocitrate dehydratase ((R)-homocitrate = cis-homoaconitate + H2O) and the LysW-dependent ligase, kinase, reductase, transaminase and hydrolase reactions; the route-specific BP terms are obsolete. Representative members from mixed Thermus thermophilus strains (HB27 and HB8) are used because reviewed UniProt entries exist for different strains.