As text, or see rules and steps
# Propionate degradation in GapMind is based on # MetaCyc pathways for the 2-methylcitrate cycle (metacyc:PWY0-42, metacyc:PWY-5747) # and for propanoyl-CoA degradation (metacyc:PROPIONMET-PWY, metacyc:PWY-7574). putP propionate transporter; proline:Na+ symporter curated:SwissProt::P07117 # Transporters were identified using: # query: transporter:propionate:propanoate propionate-transport: putP SLC5A8 sodium-coupled monocarboxylate transporter curated:SwissProt::Q8N695 propionate-transport: SLC5A8 # Shewana3_2904 (A0KZB2) from Shewanella sp. ANA-3 is important for propionate utilization; # it is also a lactate permease. # Similarly, the distantly related SO0827 from Shewanella oneidensis (Q8EIL2) is # important for propionate utilization. lctP propionate permease uniprot:A0KZB2 uniprot:Q8EIL2 propionate-transport: lctP mctC propionate:H+ symporter curated:SwissProt::Q8NS49 propionate-transport: mctC mctP propionate permease curated:TCDB::Q8VM88 curated:SwissProt::Q1M7A2 propionate-transport: mctP # Pdr12p is an exporter, ignored # Also ignore Best1, a Ca2+ activated anion channel pccA propionyl-CoA carboxylase, alpha subunit curated:BRENDA::P05165 curated:BRENDA::Q19842 curated:SwissProt::I3R7G3 curated:SwissProt::P0DTA4 curated:SwissProt::Q5LUF3 curated:SwissProt::Q91ZA3 curated:metacyc::MONOMER-13589 curated:metacyc::MONOMER-8606 curated:reanno::Dino:3607308 curated:reanno::PS:Dsui_0516 ignore_other:6.4.1.3 pccB propionyl-CoA carboxylase, beta subunit curated:BRENDA::P05166 curated:BRENDA::Q20676 curated:BRENDA::Q9X4K7 curated:SwissProt::I3R7F1 curated:SwissProt::P53003 curated:SwissProt::P79384 curated:SwissProt::Q168G2 curated:SwissProt::Q3J4E3 curated:SwissProt::Q99MN9 curated:metacyc::MONOMER-13598 curated:metacyc::MONOMER-16260 curated:metacyc::MONOMER-17283 curated:metacyc::MONOMER-17284 curated:metacyc::MONOMER-8607 curated:reanno::Dino:3607303 curated:reanno::PS:Dsui_0517 ignore_other:6.4.1.3 # propionyl-CoA carboxylase is a heteromer, usually with alpha and beta subunits pccAB. # Haloferax mediterranei has a third subunit as well (pccX), which is not described here. propionyl-CoA-carboxylase: pccA pccB pccA1 propionyl-CoA carboxylase, biotin carboxyl carrier subunit curated:metacyc::MONOMER-13597 ignore_other:6.4.1.3 pccA2 propionyl-CoA carboxylase, biotin carboxylase subunit curated:metacyc::MONOMER-13596 ignore_other:6.4.1.3 # Acidianus brierleyi has a diverged pccA split into two pieces. propionyl-CoA-carboxylase: pccA1 pccA2 pccB # Many acetyl-CoA synthetases (EC:6.2.1.1) are also propionyl-CoA synthetases prpE propionyl-CoA synthetase EC:6.2.1.17 ignore_other:6.2.1.1 # P45858 is annotated by SwissProt as 2-methylcitrate synthase, but without this EC number prpC 2-methylcitrate synthase EC:2.3.3.5 curated:BRENDA::P45858 prpD 2-methylcitrate dehydratase EC:4.2.1.79 # (2R,3S)-2-methylcitrate dehydratases are closely related to # aconitate hydratases (EC:4.2.1.3), which are ignored. acn (2R,3S)-2-methylcitrate dehydratase EC:4.2.1.99 ignore_other:4.2.1.3 # Many 2-methylisocitrate lyases are closely related to isocitrate lyases (EC:4.1.3.1) prpB 2-methylisocitrate lyase EC:4.1.3.30 ignore_other:4.1.3.1 # acnM from Ralstonia eutropha (Q937N8) is proposed to have this activity as well (PMID:11495997), but is # annotated in SwissProt as aconitase or (2R,3S)-2-methylisocitrate dehydratase instead acnD 2-methylcitrate dehydratase (2-methyl-trans-aconitate forming) EC:4.2.1.117 ignore:SwissProt::Q937N8 # SwissProt annotates Q937N7 with this activity, but with a vague EC number. # The periplasmic substrate-binding protein A0A0A1H8I4 has aconitate # isomerase activity but has a high Km (PMID:26293748), and its # periplasmic location would prevent it from participating in the # methylcitrate cycle, so it is ignored. prpF methylaconitate isomerase EC:5.3.3.7 curated:SwissProt::Q937N7 ignore:SwissProt::A0A0A1H8I4 # In the fitness browser reannotations, Dshi_0724 from Dinoroseobacter # shibae (Dino:3607309) was annotated as the epimerase because it was # annotated as such by SEED and it has a specific phenotype on # propionate, which seemed to confirm its annotation. But Dshi_0724 # belongs to the uncharacterized family DUF4174 / PF13778 and has a # signal peptide. Also, D. shibae contains another, apparently # essential, epi (Dshi_2630). epi methylmalonyl-CoA epimerase EC:5.1.99.1 ignore:reanno::Dino:3607309 mcmA methylmalonyl-CoA mutase, fused catalytic and adenosylcobamide-binding components curated:SwissProt::O86028 curated:BRENDA::P22033 curated:BRENDA::Q23381 curated:BRENDA::Q84FZ1 curated:BRENDA::Q8MI68 curated:SwissProt::P27253 curated:SwissProt::Q3J4D7 curated:metacyc::MONOMER-18293 curated:reanno::PS:Dsui_0519 curated:BRENDA::Q8F222 curated:BRENDA::Q8Y2U5 ignore_other:5.4.99.2 mcm-large methylmalonyl-CoA mutase, large (catalytic) subunit curated:BRENDA::A4YEG1 curated:BRENDA::O74009 curated:BRENDA::P11653 ignore_other:5.4.99.2 mcm-small methylmalonyl-CoA mutase, small (adenosylcobamide-binding) subunit curated:BRENDA::A4YIE3 curated:BRENDA::O58013 ignore_other:5.4.99.2 # methylmalonyl-CoA mutase has a catalytic domain and a B12-binding domain. # These are usually found in the same protein, which we call mcmA. # In Metallosphaera and Pyrococcus, the B12-binding domain is a separate subunit. # In Propionibacterium and Methylorubrum, there is an additional subunit with # a catalytic domain only; this may have a protective role # (PMID:14734568) and is not described here. # There's also a mcm-interacting GTPase (known as MeaB or YgfD) that # loads B12 onto mcm and protects it from inactivation (see # PMC4631608); this is not described here. Some fused mcm proteins include # a MeaB domain as well (i.e., uniprot:Q8F222, uniprot:Q8Y2U5). methylmalonyl-CoA-mutase: mcmA methylmalonyl-CoA-mutase: mcm-large mcm-small pco propanyl-CoA oxidase EC:1.3.3.6 hpcD 3-hydroxypropionyl-CoA dehydratase EC:4.2.1.116 dddA 3-hydroxypropionate dehydrogenase EC:1.1.1.59 # Ignore similarity to methylmalonate semialdehyde dehydrogenase (EC:1.2.1.27), which often has this activity as well iolA malonate semialdehyde dehydrogenase (CoA-acylating) EC:1.2.1.18 ignore_other:1.2.1.27 ignore:SwissProt::Q9I702 # In 2-methylcitrate cycle I, # propionyl-CoA is combined with oxalacetate (by prpC) to give methylcitrate, # dehydrated to cis-2-methylaconitate by prpD, # hydrated to (2R,3S)-2-methylisocitrate, # and a lyase produces pyruvate and succinate. # (We consider succinate as a central intermediate, # as most organisms can activate it to succinyl-CoA # or can oxidize it to fumarate and convert that to oxaloacetate.) propionyl-CoA-degradation: prpC prpD acn prpB # In 2-methylcitrate cycle II, a different dehydratase (acnD) and an isomerase (prpF) replace the # dehydratase prpD; acnD dehydrates (2S,3S)-2-methylcitrate to # 2-methyl-trans-aconitate, and prpF isomerizes it to # cis-2-methylaconitate. propionyl-CoA-degradation: prpC acnD prpF acn prpB # In propanoyl CoA degradation I, propionyl-CoA carboxylase # forms (S)-methylmalonyl-CoA, # methylmalonyl-CoA epimerase forms (R)-methylmalonyl-CoA, and # methylmalonyl-CoA mutase forms succinyl-CoA, which is a central # metabolite. (Note that methylmalonyl-CoA mutase requires # adenosylcobamide, a form of vitamin B12, for activity.) propionyl-CoA-degradation: propionyl-CoA-carboxylase epi methylmalonyl-CoA-mutase # In propanoyl-CoA degradation II: # propionyl-CoA is oxidized to acrylyl-CoA by pco, hydrated # to 3-hydroxypropionyl-CoA, hydrolzed to 3-hydroxypropionate, # oxidized to 3-oxopropionate (malonate semialdehyde), and # oxidized to acetyl-CoA and CO2. propionyl-CoA-degradation: pco hpcD dddA iolA # In all of the pathways, propionate is first activated to propionyl-CoA by prpE propionate-degradation: prpE propionyl-CoA-degradation all: propionate-transport propionate-degradation
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 the paper from 2019 on GapMind for amino acid biosynthesis, the paper from 2022 on GapMind for carbon sources, or view the source code.
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