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))
- Ignore hits to Q46133 when looking for 'other' hits (aspartate kinase (EC 2.7.2.4))
- 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?). In Corynebacterium, aspartate kinase has two subunits, both apparently encoded by the same gene by using start codons (PMID:1956296); Q46133 is the shorter regulatory subunit and lacks the catalytic domain, so it does not suffice for activity and is ignored.
- Total: 3 HMMs and 36 characterized proteins
asd: aspartate semi-aldehyde dehydrogenase
dapA: 4-hydroxy-tetrahydrodipicolinate synthase
- Curated proteins or TIGRFams with EC 4.3.3.7
- Curated proteins or TIGRFams with EC 4.2.1.52
- Ignore hits to Q3MFY8 when looking for 'other' hits (4-hydroxy-tetrahydrodipicolinate synthase (EC 4.3.3.7))
- Ignore hits to Q3M723 when looking for 'other' hits (4-hydroxy-tetrahydrodipicolinate reductase (EC 1.17.1.8))
- Ignore hits to A9CGZ4 when looking for 'other' hits (4-hydroxy-tetrahydrodipicolinate synthase (EC 4.3.3.7))
- Ignore hits to A9CHR2 when looking for 'other' hits (4-hydroxy-tetrahydrodipicolinate synthase (EC 4.3.3.7))
- Ignore hits to A9CL94 when looking for 'other' hits (4-hydroxy-tetrahydrodipicolinate synthase (EC 4.3.3.7))
- Ignore hits to A9CL97 when looking for 'other' hits (4-hydroxy-tetrahydrodipicolinate synthase (EC 4.3.3.7))
- Ignore hits to Q7D0E8 when looking for 'other' hits (4-hydroxy-tetrahydrodipicolinate synthase (EC 4.3.3.7))
- Ignore hits to Q7D313 when looking for 'other' hits (4-hydroxy-tetrahydrodipicolinate synthase (EC 4.3.3.7))
- Ignore hits to Q8A3Z0 when looking for 'other' hits (4-hydroxy-tetrahydrodipicolinate synthase (EC 4.3.3.7))
- Comment: Q3MFY8, Q3M723, and many proteins form Agrobacterium tumefaciens are misannotated in BRENDA, and are ignored. (The reference for those points at gene 1133062 = Atu1024 as the synthase instead, and states that the other Agrobacterium dapA-like proteins lack this activity, see PMID:24677246.) Q8A3Z0 is annotated as this in BRENDA, but the cited paper does not demonstrate this activity, and another protein (BT0895) appears to be the major dapA in Bacteroides thetaiotaomicron, (it is essentail), so Q8A3Z0 is ignored.
- Total: 1 HMMs and 23 characterized proteins
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};
- Curated sequence Q3MFY8: 4-hydroxy-tetrahydrodipicolinate synthase (EC 4.3.3.7)
- Ignore hits to Q3M723 when looking for 'other' hits (4-hydroxy-tetrahydrodipicolinate reductase (EC 1.17.1.8))
- 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. Q3MFY8 is misannotated in BRENDA, so it is added manually. Q3M723 is misannotated in BRENDA, so it is ignored.
- Total: 2 HMMs and 18 characterized proteins
dapD: tetrahydrodipicolinate succinylase
dapC: N-succinyldiaminopimelate aminotransferase
- Curated proteins or TIGRFams with EC 2.6.1.17
- Curated proteins or TIGRFams with EC 2.6.1.52
- Ignore hits to O50434 when looking for 'other' hits (Probable aminotransferase Rv1178; EC 2.6.1.-)
- Ignore hits to items matching EC 2.6.1.81 when looking for 'other' hits
- Comment: 2.6.1.52 is the EC number for 3-phosphoserine aminotransferase (serC), which catalyzes this reaction in E. coli. The function of O50434 is not known, so similarity to it is ignored. E.coli's succinylornithine transaminase has this activity as well (PMID:25243376), so similarity to succinylornithine transaminases (EC 2.6.1.81) is ignored.
- Total: 6 HMMs and 25 characterized proteins
dapE: succinyl-diaminopimelate desuccinylase
- Curated proteins or TIGRFams with EC 3.5.1.18
- Predicted: UniProt sequence L0FXC2: SubName: Full=Amidohydrolase {ECO:0000313|EMBL:AGA77693.1};
- Comment: DapE is missing in several genera of Bacteroidota, and a search for conserved essential genes identified the putative aminohydrolase Echvi_1427 (L0FXC2)as a candidate. This protein is 43% identical to the dipeptidase DradM20D (PMID:26456402) and 42% identical to an carboxypeptidase/aminoacylase from Pyrococcus horikoshii (PMC92634); it also has more distant homology to N-acetyl-L,L-diaminopimelate deactylase; these are all very similar reactions. Echvi_1427 has conserved active site residues and docking N-succinyl-L,L-diaminopimelate to its predicted structure with AutoDock Vina gave predicted binding (-6.5 kcal/mol) with the amide bond near the catalytic arginine (R264).
- Total: 2 HMMs and 9 characterized proteins
dapF: diaminopimelate epimerase
- Curated proteins or TIGRFams with EC 5.1.1.7
- Predicted: UniProt sequence A0A9Q5JK70: SubName: Full=Alanine racemase {ECO:0000313|EMBL:OFQ71504.1};
- Comment: L,L-diaminopimelate to meso-diaminopimelate. A putative amino acid racemase (A0A9Q5JK70) is in a conserved operon with lysA ("dapF2" in PMC9026213); it is likely to be a diaminopimelate epimerase.
- Total: 1 HMMs and 8 characterized proteins
lysA: diaminopimelate decarboxylase
- Curated proteins or TIGRFams with EC 4.1.1.20
- Ignore hits to A0A0H3H393 when looking for 'other' hits (lysine decarboxylase (EC 4.1.1.18))
- Predicted: UniProt sequence U7D9L6: SubName: Full=Diaminopimelate decarboxylase {ECO:0000313|EMBL:ERP38717.1};
- Ignore hits to MONOMER-21197 when looking for 'other' hits (dimethylsulfonio-2-hydroxybutanoate hydroxylase/decarboxylase)
- Comment: A0A0H3H393 is reported to be a lysine decarboxylase but is 87% identical to E. coli's diaminopimelate decarboxylase, so it is ignored. CALK_RS03395 (U7D9L6) has conserved functional residues (see alignment to 1ko0A) and is in an operon with meso-diaminopimelate D-dehydrogenase (ddh), so it must be the missing lysA. MetaCyc annotates THAPSDRAFT_20613 (link), which is probably a diaminopimelate decarboxylase, as a dimethylsulfonio-2-hydroxybutanoate hydroxylase/decarboxylase, but there is no experimental evidence, so it is ignored.
- Total: 1 HMMs and 16 characterized proteins
dapH: tetrahydrodipicolinate acetyltransferase
dapX: acetyl-diaminopimelate aminotransferase
dapL: N-acetyl-diaminopimelate deacetylase
- Curated proteins or TIGRFams with EC 3.5.1.47
- Predicted: UniProt sequence Q2FH40: RecName: Full=Uncharacterized hydrolase SAUSA300_1291; EC=3.-.-.-;
- Comment: Also known as ykuR or DapeL. The putative amidohydrolase AA076_RS07060 (Q2FH40) from Staphylococcus is conserved near dapX and/or lysA and is similar to N-acetylcysteine deacetylase, so we predict that it is a N-acetyl-diaminopimelate deacetylase.
- Total: 2 characterized proteins
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: 14 characterized proteins
lysN: 2-aminoadipate:2-oxoglutarate aminotransferase
- Curated proteins or TIGRFams with EC 2.6.1.39
- Ignore hits to Q06191 when looking for 'other' hits (Aspartate aminotransferase; AAT; AspAT; Transaminase A; EC 2.6.1.1)
- Comment: 2-oxoadipate to 2-aminoadipate. Q06191 is very simlar to SMc04386, which seems to have this activity (it is required for lysine utilization), and as far as we know, Q06191 has not been tested for activity on 2-aminoadipate, so it is ignored
- Total: 9 characterized proteins
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 and/or ornithine biosynthesis. It is sometimes called the amino group carrier protein. TK0279 (Q5JFV9) from Thermococcus kodakarensis was characterized, see PMC5076833.
- Total: 5 characterized proteins
lysX: 2-aminoadipate-LysW ligase
- Curated proteins or TIGRFams with EC 6.3.2.43
- Ignore hits to A5U2Z7 when looking for 'other' hits ([amino group carrier protein]-L-2-aminoadipate ligase (EC 6.3.2.43). lysyltransferase (EC 2.3.2.3); [amino group carrier protein]-L-2-aminoadipate ligase (EC 6.3.2.43). Lysylphosphatidylglycerol biosynthesis bifunctional protein LysX; EC 6.1.1.6; EC 2.3.2.3)
- Ignore hits to P9WFU7 when looking for 'other' hits ([amino group carrier protein]-L-2-aminoadipate ligase (EC 6.3.2.43). lysyltransferase (EC 2.3.2.3); [amino group carrier protein]-L-2-aminoadipate ligase (EC 6.3.2.43). Lysylphosphatidylglycerol biosynthesis bifunctional protein LysX; EC 6.1.1.6; EC 2.3.2.3)
- UniProt sequence Q5JFW0: SubName: Full=RimK-related lysine biosynthesis protein {ECO:0000313|EMBL:BAD84467.1};
- Comment: A5U2Z7 and BRENDA::P9WFU7 are misannotated in BRENDA. TK0278 from Thermococcus kodakarensis (Q5JFW0) is bifunctional, for lysine and ornithine synthesis (PMC5076833).
- Total: 5 characterized proteins
lysZ: [LysW]-2-aminoadipate 6-kinase
- Curated proteins or TIGRFams with EC 2.7.2.17
- UniProt sequence Q5JFW2: RecName: Full=Putative [LysW]-aminoadipate/[LysW]-glutamate kinase {ECO:0000256|HAMAP-Rule:MF_02082}; EC=2.7.2.17 {ECO:0000256|HAMAP-Rule:MF_02082}; EC=2.7.2.19 {ECO:0000256|HAMAP-Rule:MF_02082};
- Comment: TK0276 from Thermococcus kodakarensis (Q5JFW2) is bifunctional, for lysine and ornithine synthesis (PMC5076833).
- Total: 4 characterized proteins
lysY: [LysW]-2-aminoadipate 6-phosphate reductase
lysJ: [LysW]-2-aminoadipate semialdehyde transaminase
- Curated proteins or TIGRFams with EC 2.6.1.118
- Curated proteins or TIGRFams with EC 2.6.1.124
- UniProt sequence Q5JFW3: RecName: Full=Putative [LysW]-aminoadipate semialdehyde/glutamate semialdehyde transaminase {ECO:0000255|HAMAP-Rule:MF_02084}; EC=2.6.1.118 {ECO:0000255|HAMAP-Rule:MF_02084}; EC=2.6.1.124 {ECO:0000255|HAMAP-Rule:MF_02084};
- Comment: TK0275 from Thermococcus kodakarensis (Q5JFW3) has also been characterized (PMC5076833).
- Total: 3 characterized proteins
lysK: [LysW]-lysine hydrolase
- Curated proteins or TIGRFams with EC 3.5.1.130
- UniProt sequence Q5JFW4: RecName: Full=Putative [LysW]-lysine/[LysW]-ornithine hydrolase {ECO:0000255|HAMAP-Rule:MF_01120}; EC=3.5.1.130 {ECO:0000255|HAMAP-Rule:MF_01120}; EC=3.5.1.132 {ECO:0000255|HAMAP-Rule:MF_01120};
- Comment: TK0274 from Thermococcus kodakarensis (Q5JFW4) is bifunctional, for lysine and ornithine synthesis (PMC5076833).
- Total: 3 characterized proteins
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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:
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