Definition of L-lysine biosynthesis
As rules and steps, or see full text
Rules
Overview: Lysine biosynthesis in GapMind is based on MetaCyc pathways L-lysine biosynthesis I via diaminopimelate (DAP) and succinylated intermediates (link), II with DAP and acetylated intermediates (link), III with DAP and no blocking group (link), V via 2-aminoadipate and LysW carrier protein (link), and VI with DAP aminotransferase (link). Most of these pathways involve tetrahydrodipicolinate and meso-diaminopimelate, with variations in how the amino group is introduced. Pathway V instead involves L-2-aminoadipate and LysW-attached intermediates. Lysine biosynthesis IV (link), via 2-aminoadipate and saccharopine, is only reported to occur in eukaryotes and is not described here.
- all:
- meso-DAP and lysA
- or lysW-pathway
- lysW-pathway: hcs, lysT, lysU, hicdh, lysN, lysW, lysX, lysZ, lysY, lysJ and lysK
- Comment: 2-oxoglutarate and acetyl-CoA are converted to homocysteine, homoaconitate and then 2-oxoadipate (by hcs-lysTU-hicdh), an aminotransferase (lysN) forms L-2-aminoadipate, lysX ligates 2-aminoadipate to lysW, lysZYJ convert LysW-aminoadipate to LysW-lysine, and lysK releases lysine.
- meso-DAP:
- aspartate-semialdehyde, dapA, dapB, dapD, dapC, dapE and dapF
- or aspartate-semialdehyde, dapA, dapB, dapH, dapX, dapL and dapF
- or aspartate-semialdehyde, dapA, dapB and ddh
- or aspartate-semialdehyde, dapA, dapB, DAPtransferase and dapF
- Comment: (S)-2,3,4,5-tetrahydrodipicolinate is formed from aspartate semialdehyde by dapAB. In pathway I (dapDCE), it is succinylated, transaminated, and desuccinyulated, to L,L-DAP, and then the epimerase dapF forms meso-DAP. Pathway II (dapHXL) is similar but with acetylated intermediates. In pathway III, tetrahydrodipicolinate is reductively aminated to meso-DAP in one step, by ddh. In pathway VI, an aminotransferase (DAPtransferase) forms L,L-DAP.
- aspartate-semialdehyde: asp-kinase and asd
Steps
asp-kinase: aspartate kinase
- Curated proteins or TIGRFams with EC 2.7.2.4
- Ignore hits to O63067 when looking for 'other' hits (homoserine dehydrogenase (EC 1.1.1.3))
- Comment: For BRENDA::O63067 -- the paper describes a monofunctional hom but the sequence of O63067 is much longer and has a close homolog of functional aspartate kinase (due to alternative splicing?)
- Total: 3 HMMs and 29 characterized proteins
asd: aspartate semi-aldehyde dehydrogenase
dapA: 4-hydroxy-tetrahydrodipicolinate synthase
dapB: 4-hydroxy-tetrahydrodipicolinate reductase
- Curated proteins or TIGRFams with EC 1.17.1.8
- UniProt sequence L0G028_ECHVK: SubName: Full=Dihydrodipicolinate reductase {ECO:0000313|EMBL:AGA78643.1};
- UniProt sequence A0A1X9Z7Q6_9SPHI: RecName: Full=4-hydroxy-tetrahydrodipicolinate reductase {ECO:0000256|HAMAP-Rule:MF_00102}; Short=HTPA reductase {ECO:0000256|HAMAP-Rule:MF_00102}; EC=1.17.1.8 {ECO:0000256|HAMAP-Rule:MF_00102};
- Comment: Formerly known as dihydrodipicolinate reductase. Echvi_2395 (L0G028_ECHVK) and CA265_RS15670 (A0A1X9Z7Q6_9SPHI) are somewhat diverged, but conserved essentiality confirms they are dapB.
- Total: 2 HMMs and 6 characterized proteins
dapD: tetrahydrodipicolinate succinylase
dapC: N-succinyldiaminopimelate aminotransferase
dapE: succinyl-diaminopimelate desuccinylase
dapF: diaminopimelate epimerase
lysA: diaminopimelate decarboxylase
dapH: tetrahydrodipicolinate acetyltransferase
dapX: acetyl-diaminopimelate aminotransferase
dapL: N-acetyl-diaminopimelate deacetylase
ddh: meso-diaminopimelate D-dehydrogenase
DAPtransferase: L,L-diaminopimelate aminotransferase
hcs: homocitrate synthase
lysT: homoaconitase large subunit
lysU: homoaconitase small subunit
hicdh: homo-isocitrate dehydrogenase
- Curated proteins or TIGRFams with EC 1.1.1.87
- Curated proteins or TIGRFams with EC 1.1.1.286
- Comment: homoisocitrate to 2-oxoadipate. This rule also matches some isocitrate/homoisocitrate dehydrogenases (1.1.1.286) which often have multiple subunits in eukaryotes; this is not represented here.
- Total: 12 characterized proteins
lysN: 2-aminoadipate:2-oxoglutarate aminotransferase
lysW: 2-aminoadipate/glutamate carrier protein
- Curated proteins matching alpha-aminoadipate%carrier
- UniProt sequence Q5JFV9: SubName: Full=Probable lysine biosynthesis protein {ECO:0000313|EMBL:BAD84468.1};
- Comment: LysW is a carrier protein for intermediates in lysine or ornithine biosynthesis. TK0279 (Q5JFV9) from Thermococcus kodakarensis was characterized, see PMC5076833.
- Total: 5 characterized proteins
lysX: 2-aminoadipate-LysW ligase
lysZ: [LysW]-2-aminoadipate 6-kinase / [LysW]-glutamate kinase
lysY: [LysW]-2-aminoadipate 6-phosphate reductase / [LysW]-glutamylphosphate reductase
lysJ: [LysW]-2-aminoadipate semialdehyde transaminase / [LysW]-glutamate semialdehyde transaminase
lysK: [LysW]-lysine hydrolase / [LysW]-ornithine hydrolase
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About GapMind
Each pathway is defined by a set of rules based on individual steps or genes. Candidates for each step are identified by using
ublast (a fast alternative to protein BLAST)
against a database of manually-curated proteins (most of which are experimentally characterized) or by using
HMMer with enzyme models (usually from
TIGRFam). Ublast hits may be split across two different proteins.
A candidate for a step is "high confidence" if either:
- ublast finds a hit to a characterized protein at above 40% identity and 80% coverage, and bits >= other bits+10.
- (Hits to curated proteins without experimental data as to their function are never considered high confidence.)
- HMMer finds a hit with 80% coverage of the model, and either other identity < 40 or other coverage < 0.75.
where "other" refers to the best ublast hit to a sequence that is not annotated as performing this step (and is not "ignored").
Otherwise, a candidate is "medium confidence" if either:
- ublast finds a hit at above 40% identity and 70% coverage (ignoring otherBits).
- ublast finds a hit at above 30% identity and 80% coverage, and bits >= other bits.
- HMMer finds a hit (regardless of coverage or other bits).
Other blast hits with at least 50% coverage are "low confidence."
Steps with no high- or medium-confidence candidates may be considered "gaps."
For the typical bacterium that can make all 20 amino acids, there are 1-2 gaps in amino acid biosynthesis pathways.
For diverse bacteria and archaea that can utilize a carbon source, there is a complete
high-confidence catabolic pathway (including a transporter) just 38% of the time, and
there is a complete medium-confidence pathway 63% of the time.
Gaps may be due to:
- our ignorance of proteins' functions,
- omissions in the gene models,
- frame-shift errors in the genome sequence, or
- the organism lacks the pathway.
GapMind relies on the predicted proteins in the genome and does not search the six-frame translation. In most cases, you can search the six-frame translation by clicking on links to Curated BLAST for each step definition (in the per-step page).
For more information, see the paper from 2019 on GapMind for amino acid biosynthesis, the paper from 2022 on GapMind for carbon sources, or view the source code, or see changes to Amino acid biosynthesis since the publication.
If you notice any errors or omissions in the step descriptions, or any questionable results, please let us know
by Morgan Price, Arkin group, Lawrence Berkeley National Laboratory