As text, or see rules and steps
# Lysine biosynthesis in GapMind is based on MetaCyc # pathways L-lysine biosynthesis I via diaminopimelate (DAP) and # succinylated intermediates (metacyc:DAPLYSINESYN-PWY), # II with DAP and acetylated intermediates (metacyc:PWY-2941), # III with DAP and no blocking group (metacyc:PWY-2942), # V via 2-aminoadipate and LysW carrier protein (metacyc:PWY-3081), # and VI with DAP aminotransferase (metacyc:PWY-5097). # 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 (metacyc:LYSINE-AMINOAD-PWY), via 2-aminoadipate and saccharopine, # is only reported to occur in eukaryotes and is not described here. import met.steps:aspartate-semialdehyde # uniprot:Q3MFY8, uniprot: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.) # uniprot: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. dapA 4-hydroxy-tetrahydrodipicolinate synthase EC:4.3.3.7 EC:4.2.1.52 ignore:BRENDA::Q3MFY8 ignore:BRENDA::Q3M723 ignore:BRENDA::A9CGZ4 ignore:BRENDA::A9CHR2 ignore:BRENDA::A9CL94 ignore:BRENDA::A9CL97 ignore:BRENDA::Q7D0E8 ignore:BRENDA::Q7D313 ignore:BRENDA::Q8A3Z0 # Formerly known as dihydrodipicolinate reductase. # Echvi_2395 (uniprot:L0G028_ECHVK) and CA265_RS15670 (uniprot:A0A1X9Z7Q6_9SPHI) are somewhat diverged, # but conserved essentiality confirms they are dapB. # uniprot:Q3MFY8 is misannotated in BRENDA, so it is added manually. # uniprot:Q3M723 is misannotated in BRENDA, so it is ignored. dapB 4-hydroxy-tetrahydrodipicolinate reductase EC:1.17.1.8 uniprot:L0G028_ECHVK uniprot:A0A1X9Z7Q6_9SPHI curated:BRENDA::Q3MFY8 ignore:BRENDA::Q3M723 # Formerly known as 2,3,4,5-tetrahydropyridine-2-carboxylate N-succinyltransferase dapD tetrahydrodipicolinate succinylase EC:2.3.1.117 # 2.6.1.52 is the EC number for 3-phosphoserine aminotransferase (serC), which catalyzes # this reaction in E. coli. # The function of uniprot: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. dapC N-succinyldiaminopimelate aminotransferase EC:2.6.1.17 EC:2.6.1.52 ignore:SwissProt::O50434 ignore_other:EC 2.6.1.81 # DapE is missing in several genera of Bacteroidota, and a search for # conserved essential genes identified the putative aminohydrolase # Echvi_1427 (uniprot: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). dapE succinyl-diaminopimelate desuccinylase EC:3.5.1.18 predicted:L0FXC2 # 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. dapF diaminopimelate epimerase EC:5.1.1.7 predicted:A0A9Q5JK70 # A0A0H3H393 is reported to be a lysine decarboxylase but is 87% identical to E. coli's # diaminopimelate decarboxylase, so it is ignored. # CALK_RS03395 (uniprot: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 (metacyc:MONOMER-21197), which is probably a diaminopimelate decarboxylase, # as a dimethylsulfonio-2-hydroxybutanoate hydroxylase/decarboxylase, but there is no experimental evidence, so # it is ignored. lysA diaminopimelate decarboxylase EC:4.1.1.20 ignore:BRENDA::A0A0H3H393 predicted:U7D9L6 ignore:metacyc::MONOMER-21197 # Also known as ykuQ dapH tetrahydrodipicolinate acetyltransferase EC:2.3.1.89 # Also known as patA in Bacillus subtilis dapX acetyl-diaminopimelate aminotransferase term:N-acetyl-LL-diaminopimelate aminotransferase # 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. dapL N-acetyl-diaminopimelate deacetylase EC:3.5.1.47 predicted:Q2FH40 # In reverse, this converts tetrahydrodipicolinate to meso-DAP. ddh meso-diaminopimelate D-dehydrogenase EC:1.4.1.16 # This enzyme is sometimes known as dapL. In reverse, it converts tetrahydrodipicolinate to L,L-DAP. DAPtransferase L,L-diaminopimelate aminotransferase EC:2.6.1.83 # forming (2R)-homocitrate hcs homocitrate synthase EC:2.3.3.14 # (2R)-homocitrate to (1R,2S)-homoisocitrate via cis-homoaconitate lysT homoaconitase large subunit term:homoaconitase large subunit ignore_other:EC 4.2.1.114 ignore_other:EC 4.2.1.36 lysU homoaconitase small subunit term:homoaconitase small subunit ignore_other:EC 4.2.1.114 ignore_other:EC 4.2.1.36 # 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. hicdh homo-isocitrate dehydrogenase EC:1.1.1.87 EC:1.1.1.286 # 2-oxoadipate to 2-aminoadipate. # uniprot: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 lysN 2-aminoadipate:2-oxoglutarate aminotransferase EC:2.6.1.39 ignore:SwissProt::Q06191 # LysW is a carrier protein for intermediates in lysine and/or ornithine biosynthesis. # It is sometimes called the amino group carrier protein. # TK0279 (uniprot:Q5JFV9) from Thermococcus kodakarensis was characterized, see PMC5076833. lysW 2-aminoadipate/glutamate carrier protein term:alpha-aminoadipate%carrier uniprot:Q5JFV9 # A5U2Z7 and BRENDA::P9WFU7 are misannotated in BRENDA. # TK0278 from Thermococcus kodakarensis (uniprot:Q5JFW0) is bifunctional, for lysine and ornithine synthesis (PMC5076833). lysX 2-aminoadipate-LysW ligase EC:6.3.2.43 ignore:BRENDA::A5U2Z7 ignore:BRENDA::P9WFU7 uniprot:Q5JFW0 # TK0276 from Thermococcus kodakarensis (uniprot:Q5JFW2) is bifunctional, for lysine and ornithine synthesis (PMC5076833). lysZ [LysW]-2-aminoadipate 6-kinase EC:2.7.2.17 uniprot:Q5JFW2 # TK0277 (uniprot:Q5JFW1) is bifunctional, for lysine and arginine synthesis (PMC5076833). lysY [LysW]-2-aminoadipate 6-phosphate reductase EC:1.2.1.103 curated:BRENDA::Q5JFW1 # TK0275 from Thermococcus kodakarensis (uniprot:Q5JFW3) has also been characterized (PMC5076833). lysJ [LysW]-2-aminoadipate semialdehyde transaminase EC:2.6.1.118 EC:2.6.1.124 uniprot:Q5JFW3 # TK0274 from Thermococcus kodakarensis (uniprot:Q5JFW4) is bifunctional, for lysine and ornithine synthesis (PMC5076833). lysK [LysW]-lysine hydrolase EC:3.5.1.130 uniprot:Q5JFW4 # (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. meso-DAP: aspartate-semialdehyde dapA dapB dapD dapC dapE dapF meso-DAP: aspartate-semialdehyde dapA dapB dapH dapX dapL dapF meso-DAP: aspartate-semialdehyde dapA dapB ddh meso-DAP: aspartate-semialdehyde dapA dapB DAPtransferase dapF # 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. lysW-pathway: hcs lysT lysU hicdh lysN lysW lysX lysZ lysY lysJ lysK all: meso-DAP lysA all: lysW-pathway
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:
Otherwise, a candidate is "medium confidence" if either:
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:
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