Definition of L-methionine biosynthesis
As rules and steps, or see full text
Rules
Overview: Methionine biosynthesis in GapMind is based on MetaCyc pathways L-methionine biosynthesis I via O-succinylhomoserine and cystathionine (link), II via O-phosphohomoserine and cystathionine (link), III via O-acetylhomoserine (link), or IV with reductive sulfhydrylation of aspartate semialdehyde (link). These pathways vary in how aspartate semialdehyde is reduced and sulfhydrylated to homocysteine. GapMind does not represent the formation of the methyl donors for methionine synthase, such as 5-methyltetrahydrofolate or methyl corrinoid proteins.
- all: homocysteine and methionine_synthase
- methionine_synthase:
- metH and B12-reactivation
- or split_metH_1, split_metH_2, split_metH_3 and B12-reactivation
- or metE
- or split_metE_1 and split_metE_2
- or mesA
- or mesB
- or mesC
- or mesD and mesX
- Comment: Besides MetH (with B-12 reactivation) or 3-part MetH as in Phaeobacter (PMC5764234), or MetE, or MetE split into two parts (PMC7857596), GapMind also includes the folate-independent systems MesA, MesB, MesC, and MesD/MesX (PMC7857596). It is possible that the corrinoid-dependent methionine synthases (MesA, MesB, or MesC) would require B12 reactivation, but this is not proven, and some methanogens with MesA seem to lack RamA, so B12 reactivation is not included. The role of split MetE or MesC lacks experimental evidence, and is based on gene neighborhoods and functional residues only (PMC7857596).
- B12-reactivation:
- B12-reactivation-domain
- or ramA
- Comment: MetH occasionally oxidizes the vitamin B12 cofactor from Co(I) to Co(II), so a reductase is needed to maintain its activity.
- homocysteine:
- aspartate-semialdehyde and asd-sulfhydrylation
- or homoserine, metX and metY
- or homoserine, metA and metZ
- or homoserine and transsulfuration
- transsulfuration:
- metA, metB and metC
- or metX, metB and metC
- or hom_kinase, metB and metC
- Comment: Transsulfuration is the conversion of homoserine to homocysteine, with the sulfur being obtained from cysteine. It is thought to occur with any of the activated forms of homoserine (O-acetyl-, O-succinyl-, or O-phospho-homoserine).
- homoserine: aspartate-semialdehyde and hom
- asd-sulfhydrylation: asd-S-transferase, asd-S-ferredoxin and asd-S-perS
- Comment: Reductive sulfhydrylation of aspartate semialdehyde to homocysteine is carried out by a multi-component system (see PMID:25315403 and PMC5764234)
- 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
hom: homoserine dehydrogenase
- Curated proteins or TIGRFams with EC 1.1.1.3
- UniProt sequence A0A1L6J6Q3: RecName: Full=Homoserine dehydrogenase {ECO:0000256|ARBA:ARBA00013213, ECO:0000256|RuleBase:RU000579}; EC=1.1.1.3 {ECO:0000256|ARBA:ARBA00013213, ECO:0000256|RuleBase:RU000579};
- UniProt sequence Q8A541_BACTN: SubName: Full=Aspartokinase/homoserine dehydrogenase {ECO:0000313|EMBL:AAO77510.1};
- UniProt sequence B8DRS3_DESVM: RecName: Full=Homoserine dehydrogenase {ECO:0000256|ARBA:ARBA00013213, ECO:0000256|RuleBase:RU000579}; EC=1.1.1.3 {ECO:0000256|ARBA:ARBA00013213, ECO:0000256|RuleBase:RU000579};
- UniProt sequence A0A168MV81: RecName: Full=homoserine dehydrogenase {ECO:0000256|ARBA:ARBA00013213}; EC=1.1.1.3 {ECO:0000256|ARBA:ARBA00013213};
- Comment: Ga0059261_2711 (A0A1L6J6Q3) from Sphingomonas koreensis DSMZ 15582 is distant from characterized homoserine dehydrogenases and is confirmed by fitness data. BT2403 from Bacteroides thetaiotaomicron (Q8A541_BACTN) is a fusion of aspartate kinase and homoserine dehydrogenase. The homoserine dehydrogenase portion is somewhat diverged. Its role is confirmed by strong cofitness with threonine synthase (the defined media for B. thetaiotaomicron included methionine). DvMF_1412 from Desulfovibrio vulgaris Miyazaki F (B8DRS3_DESVM) is a somewhat diverged homoserine dehydrogenase; it has auxotrophic phenotypes. A0A168MV81 from Brevundimonas is a somewhat diverged homoserine dehydrogenase (fused to aspartate kinase); it has auxotrophic phenotypes.
- Total: 33 characterized proteins
metA: homoserine O-succinyltransferase
- Curated proteins or TIGRFams with EC 2.3.1.46
- Comment: As discussed in PMID:28581482, many members of the MetA family are actually homoserine O-acetyltransferases, and many members of the MetX family are actually homoserine O-succinyltransferases. Fortunately, many enzymes of both types have been curated in Swiss-Prot.
- Total: 1 HMMs and 34 characterized proteins
metX: homoserine O-acetyltransferase
- Curated proteins or TIGRFams with EC 2.3.1.31
- Comment: MetX is often encoded next to a methyltransferase-like protein MetW. Because MetW is not consistently required for MetX's activity, it is not included in GapMind. MetW can bind MetX and increase its activity (PMID:33604638), and in some bacteria, there is tight cofitness between MetX and MetW, which suggests that MetW is required for MetX's activity (i.e., Paraburkholderia bryophila, many Pseudomonas, Caulobacter crescentus, or Sphingomonas koreensis). But in other diverse bacteria, metW mutants can still grow in minimal media (i.e., Herbaspirillum seropedicae or Cupriavidus necator), or have milder phenotypes than metX mutants (i.e., Burkholderia phytofirmans, Acidovorax 3H11, Dechlorosoma suillum PS, Marinobacter adhaerens).
- Total: 1 HMMs and 68 characterized proteins
hom_kinase: homoserine kinase
metB: cystathionine gamma-synthase
- Curated proteins or TIGRFams with EC 2.5.1.48
- Curated sequence O31631: Cystathionine gamma-synthase/O-acetylhomoserine (thiol)-lyase; CGS/OAH thiolyase; O-acetylhomoserine sulfhydrylase; OAH sulfhydrylase; EC 2.5.1.-
- Ignore hits to Q1M0P5 when looking for 'other' hits (Cystathionine gamma-synthase; CGS; O-succinylhomoserine (thiol)-lyase; EC 2.5.1.48. cystathionine gamma-synthase (EC 2.5.1.48))
- Comment: Many metB proteins have some activity as O-succinylhomoserine sulfhydrylase (metZ) as well, and many metZ proteins are annotated with this EC number. So this step may include both enzymes. METI_BACSU (O31631) has activity as CGS but is given a more vague EC number. Q1M0P5 is now thought to be a gamma-lyase instead (see link_RS00540-MONOMER), so it is ignored.
- Total: 1 HMMs and 14 characterized proteins
metC: cystathionine beta-lyase
- Curated proteins or TIGRFams with EC 4.4.1.13
- Ignore hits to Q84UD0 when looking for 'other' hits (cysteine-S-conjugate beta-lyase (EC 4.4.1.13); L-cystine beta-lyase (EC 4.4.1.35))
- Ignore hits to Q9EYM7 when looking for 'other' hits (cysteine-S-conjugate beta-lyase (EC 4.4.1.13))
- Ignore hits to Q9SIV0 when looking for 'other' hits (S-alkyl-thiohydroximate lyase SUR1; Protein ABERRANT LATERAL ROOT FORMATION 1; Protein HOOKLESS 3; Protein ROOTY; Protein ROOTY 1; Protein SUPERROOT 1; EC 4.4.1.-. alkyl-thiohydroximate C-S lyase (EC 4.4.1.13))
- Ignore hits to CH_088676 when looking for 'other' hits (cystathionine beta-lyase; EC 4.4.1.8)
- Ignore hits to Q46061 when looking for 'other' hits (L-cysteine desulfidase (EC 4.4.1.28))
- Curated sequence Q5H4T8: cystathionine gamma-lyase (EC 4.4.1.1)
- Comment: BRENDA annotates Q84UD0 with this EC number but it may be a cystine lyase only (PMID:12525491). BRENDA annotates Q9EYM7 with this EC but it appears to be a cystathionine beta synthase (PMID:12101301). Q9SIV0 appears to be specific to glucosinolate biosynthesis. CH_088676 is annotated as this but with a different EC number, so it is ignored. Q4606 is annotated as cysteine desulfidase but is nearly identical to Q93QC6, which is a cystathionine beta-lyase, so it is ignored. XoMetC (Q5H4T8) is annotated as a gamma-lyase by BRENDA, but it also has beta-lyase activity (PMID:24531493).
- Total: 30 characterized proteins
metY: O-acetylhomoserine sulfhydrylase
- Curated proteins or TIGRFams with EC 2.5.1.49
- Curated sequence O31631: Cystathionine gamma-synthase/O-acetylhomoserine (thiol)-lyase; CGS/OAH thiolyase; O-acetylhomoserine sulfhydrylase; OAH sulfhydrylase; EC 2.5.1.-
- Ignore hits to items matching O-succinylhomoserine sulfhydrylase when looking for 'other' hits
- Curated sequence CH_123612: O-acetylhomoserine O-acetylserine sulphydrylase
- Curated sequence Q9WZY4: O-acetyl-L-homoserine sulfhydrylase; OAH sulfhydrylase; O-acetylhomoserine thiolase; EC 2.5.1.-
- Curated sequence Q5SK88: O-acetyl-L-homoserine sulfhydrylase 1; OAH-sulfhydrylase 1; EC 2.5.1.-
- UniProt sequence A0A2T5J8K7: SubName: Full=O-acetylhomoserine (Thiol)-lyase {ECO:0000313|EMBL:PTQ95791.1};
- Comment: METI_BACSU (O31631) has activity as OAS but is given a more vague EC number. CH_123612, Q9WZY4, and Q5SK88 are annotated as this but without the EC number. In Mucilaginibacter yixingensis YX-36, C8P68_RS15690 is important for fitness in minimal media; it is usually annotated as O-succinylhomoserine sulfhydrylase, but the acylating enzmye (C8P68_RS13005) is similar to O-acetyltransferases and has the correct functional residues (i.e., similar to H1YC36 in supplementary data set 3 of PMID:28581482); so it must be an o-acetylhomoserine sulfhydrylase.
- Total: 16 characterized proteins
metZ: O-succinylhomoserine sulfhydrylase
metE: vitamin B12-independent methionine synthase
split_metE_1: vitamin B12-independent methionine synthase, folate-binding component
- Predicted: UniProt sequence G0EDA1_PYRF1: SubName: Full=Cobalamin-independent synthase MetE domain protein {ECO:0000313|EMBL:AEM39779.1};
- Predicted: UniProt sequence D4GW95: SubName: Full=5-methyltetrahydropteroyltriglutamate--homocysteine S-methyltransferase (Methionine synthase II) {ECO:0000313|EMBL:ADE02584.1}; EC=2.1.1.14 {ECO:0000313|EMBL:ADE02584.1};
- Comment: In many thermophilic archaea, MetE seems to be split into two pieces (PMC7857596). There is experimental support for a protein complex (PMC2668238), and the two pieces often appear to form an operon, but there is no experimental evidence that they are a methionine synthase. We added the gene from Haloferax volcanii (D4GW95) as it is diverged but is conserved next to a catalytic component with correct functional residues (D4GW90).
split_metE_2: vitamin B12-independent methionine synthase, catalytic component
- Predicted: UniProt sequence G0EFB7_PYRF1: RecName: Full=Methionine synthase {ECO:0000256|HAMAP-Rule:MF_00288}; EC=2.1.1.- {ECO:0000256|HAMAP-Rule:MF_00288}; AltName: Full=Homocysteine methyltransferase {ECO:0000256|HAMAP-Rule:MF_00288};
- Predicted: UniProt sequence D4GW90: RecName: Full=Methionine synthase {ECO:0000256|HAMAP-Rule:MF_00288}; EC=2.1.1.- {ECO:0000256|HAMAP-Rule:MF_00288}; AltName: Full=Homocysteine methyltransferase {ECO:0000256|HAMAP-Rule:MF_00288};
- Comment: In many thermophilic archaea, MetE seems to be split into two pieces (see PMC7857596). The catalytic component has the necessary zinc-binding residues (H219, C221, C307) and homocysteine-binding residues (S20, E71, D185). We added the gene from Haloferax volcanii (D4GW90) as it has the correct functional residues and is conserved next to a potential folate-binding component (D4GW90).
metH: vitamin B12-dependent methionine synthase
- Curated proteins or TIGRFams with EC 2.1.1.13
- Ignore hits to GFF1501 when looking for 'other' hits (ATP-dependent reduction of co(II)balamin (RamA-like) (EC:2.1.1.13))
- Ignore hits to GFF1318 when looking for 'other' hits (Accessory protein for co(II)balamin reduction (DUF1638) (EC:2.1.1.13))
- Ignore hits to GFF1321 when looking for 'other' hits (Methionine synthase component, methyltransferase domain (EC:2.1.1.13))
- Ignore hits to GFF1319 when looking for 'other' hits (Methionine synthase component, B12 binding and B12-binding cap domains (EC:2.1.1.13))
- Ignore hits to GFF1582 when looking for 'other' hits (Methionine synthase component, pterin-binding domain (EC:2.1.1.13))
- UniProt sequence Q72BP9_DESVH: RecName: Full=Methionine synthase {ECO:0000256|ARBA:ARBA00013998}; EC=2.1.1.13 {ECO:0000256|ARBA:ARBA00012032}; AltName: Full=5-methyltetrahydrofolate--homocysteine methyltransferase {ECO:0000256|ARBA:ARBA00031040};
- UniProt sequence B8DKK4_DESVM: RecName: Full=Methionine synthase {ECO:0000256|ARBA:ARBA00013998}; EC=2.1.1.13 {ECO:0000256|ARBA:ARBA00012032}; AltName: Full=5-methyltetrahydrofolate--homocysteine methyltransferase {ECO:0000256|ARBA:ARBA00031040};
- Comment: Desulfovibrio have a somewhat diverged MetH, without the activation domain, but confirmed by cofitness (DVU1585 = Q72BP9_DESVH is cofit with MetF; DvMF_0476 = B8DKK4_DESVM is cofit with a RamA- like activation protein). 3-part split MetH proteins from Phaeobacter are ignored.
- Total: 1 HMMs and 9 characterized proteins
split_metH_1: Methionine synthase component, B12 binding and B12-binding cap domains
- Curated sequence GFF1319: Methionine synthase component, B12 binding and B12-binding cap domains (EC:2.1.1.13)
- Comment: In Phaeobacter and some related bacteria, MetH is split into 3 parts (PMC5764234)
- Total: 1 characterized proteins
split_metH_2: Methionine synthase component, methyltransferase domain
split_metH_3: Methionine synthase component, pterin-binding domain
B12-reactivation-domain: MetH reactivation domain
- HMM PF02965
- Ignore hits to items matching EC 2.1.1.13 when looking for 'other' hits
- Predicted: UniProt sequence A0A6I3SQJ4: SubName: Full=Methionine synthase {ECO:0000313|EMBL:MTV50682.1};
- Comment: In E. coli and many other bacteria, the MetH protein includes a reactivation domain (PF02965), but other ATP-dependent (ramA-like) activation proteins are also thought to exist. Ignore MetH proteins, as they often contain the reactivation domain and this creates confusion when checking for reverse hits. In Heliobacterium modesticaldum, the missing reactivation domain is probably provided by H1S01_RS06050 (very similar to A0A6I3SQJ4), which does not hit the HMM but for PF02965 but is found by PFam-N or foldseek, and is usually encoded to next to MetH.
- Total: 1 HMMs
ramA: ATP-dependent reduction of co(II)balamin
- HMM PF14574
- Curated proteins matching ATP-dependent reduction of co(II)balamin
- Comment: As of April 2019, all characterized members of the RamA family or PF14574 are involved in the reactivation of co(II)balamin. This includes RamA (B8Y445), DvMF_1398, PGA1_c15200, and ELI_0370 (part of a O-demethylase). Many bacteria contain MetH and probably rely on a distant homolog of RamA for reactivation of B-12. PF14574 describes only the C-terminal putative ATPase domain of RamA, but no other functions are known, except for the reactivation of Co(II) corrinoid proteins (i.e. RamQ, P0DX10).
- Total: 1 HMMs and 3 characterized proteins
asd-S-transferase: L-aspartate semialdehyde sulfurtransferase, persulfide component
- Curated sequence Q8TPT4: L-aspartate semialdehyde sulfurtransferase (EC 2.8.1.16). L-aspartate semialdehyde sulfurtransferase; EC 2.8.1.16. L-aspartate semialdehyde sulfurtransferase (EC 2.8.1.16)
- Curated sequence 8500721: Homocysteine formation from aspartate semialdehyde (DUF39 component)
- Curated sequence Q57564: L-aspartate semialdehyde sulfurtransferase (EC 2.8.1.16). L-aspartate semialdehyde sulfurtransferase; EC 2.8.1.16
- Comment: In the reductive sulfuration of aspartate semialdehyde, the sulfurtransferase component is MA1821 or DvMF_1464 (see PMID:25315403 and PMC5764234) or Q57564 (from SwissProt). Although this reaction has not been biochemically demonstrated, a distant homolog performs a similar reaction, converting sulfoacetaldehyde to coenzyme M (see MJ1681 and PMID:30932481). (This family was formerly DUF39.)
- Total: 3 characterized proteins
asd-S-ferredoxin: L-aspartate semialdehyde sulfurtransferase, NIL/ferredoxin component
- Curated sequence Q8TPT3: L-aspartate semialdehyde sulfurtransferase iron-sulfur subunit
- Curated sequence 8499492: Homocysteine formation from aspartate semialdehyde (NIL/ferredoxin component)
- Predicted: UniProt sequence A6UQ02: SubName: Full=4Fe-4S ferredoxin iron-sulfur binding domain protein {ECO:0000313|EMBL:ABR54574.1};
- Comment: The NIL/ferredoxin component is MA1822 or DvMF_0262 (see PMID:25315403 and PMC5764234). In Methanococcus, this component (MEVAN_RS03425, A6UQ02) is diverged but is in a conserved operon with the sulfurtransferase component.
- Total: 2 characterized proteins
asd-S-perS: L-aspartate semialdehyde sulfurtransferase, persulfide-forming component
- UniProt sequence Y1715_METAC: RecName: Full=UPF0280 protein MA_1715 {ECO:0000255|HAMAP-Rule:MF_01079};
- Curated sequence 8499265: Homocysteine formation from aspartate semialdehyde (COG2122 or apbE like component)
- Predicted: UniProt sequence F2LX84: SubName: Full=ApbE family lipoprotein {ECO:0000313|EMBL:AEA33142.1};
- Comment: The putative persulfide forming component is MA1715 or DvMF_0044 (see PMID:25315403 and PMC5764234). A conserved cysetien in MA1821 is modified to a persulfide in vivo (PMID:28165724). This component is not 100% required in Methanosarcina acetivorans (possible redundancy). In Hippea alviniae, this protein (G415_RS0107280, similar to F2LX84) is diverged but is in an operon with the other components.
- Total: 2 characterized proteins
mesA: Methylcobalamin:homocysteine methyltransferase MesA
- Curated sequence P55299: Methionine synthase; Homocysteine methyltransferase; Methylcobalamin:homocysteine methyltransferase; EC 2.1.1.-. MtrA-dependent methionine synthase
- Comment: Methanogens have a short homolog of MetE that transfers methyl groups from methylcobalamin (not 5-methyltetrahydrofolates) to homocysteine to form methionine (PMID:10469143). We named this family of "core" methioine synthases MesA and proposed that MtrA (the corrinoid subunit of methyltetrahydromethanopterin:coenzyme M methyltransferase) is the physiological methyl donor (PMC7857596).
- Total: 1 characterized proteins
mesB: Methylcobalamin:homocysteine methyltransferase MesB
- Curated sequence MONOMER-21502: [corrinoid iron-sulfur protein]-dependent methionine synthase
- Comment: Another core methionine synthase (distantly related to MesA) has been characterized in Dehalococcoides (PMC7005905). It probably obtains methyl groups from the iron-sulfur corrinoid protein of the Wood-Ljungdahl pathway (CoFeSP), but this is not proven. We named this family MesB (PMID:33534785).
- Total: 1 characterized proteins
mesC: Methylcobalamin:homocysteine methyltransferase MesC
- Predicted: UniProt sequence Q8TUL3_METAC: RecName: Full=5-methyltetrahydropteroyltriglutamate--homocysteine methyltransferase {ECO:0008006|Google:ProtNLM};
- Comment: MesC is another family of core methionine synthases, without experimental evidence, but with the correct functional residues, and linked to the Wood-Ljungdahl pathway by the gene neighbor method (PMC7857596). The corrinoid protein of the Wood-Ljungdahl pathway is probably the methyl donor.
mesD: oxygen-dependent methionine synthase, methyltransferase component MesD
- UniProt sequence Q6F6Z8: SubName: Full=5-methyltetrahydropteroyltriglutamate-homocysteine methyltransferase {ECO:0000313|EMBL:CAG70167.1}; EC=2.1.1.14 {ECO:0000313|EMBL:CAG70167.1};
- Curated sequence Ga0059261_2929: oxygen-dependent methionine synthase, methyltransferase component MesD
- Comment: Genetic evidence shows that ACIAD3523 and Ga0059261_2929 are methionine synthases, see PMC2290942 and PMID:33534785. They require mesX (ACIAD3524 or Ga0059261_2928) and oxygen for activity, but not 5-methyltetrahydrofolates or cobalamin.
- Total: 2 characterized proteins
mesX: oxygen-dependent methionine synthase, putative oxygenase component MesX
- UniProt sequence Q6F6Z7: RecName: Full=DUF1852 domain-containing protein {ECO:0008006|Google:ProtNLM};
- Curated sequence Ga0059261_2928: oxygen-dependent methionine synthase, putative oxygenase component MesX
- Comment: MesX is required for the activity of MesD, see PMC2290942.
- Total: 2 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