Family Search for PF06500 (FrsA-like)

April 2024: See Interactive Tools for Functional Annotation of Bacterial Genomes for advice on using these tools.

PF06500 hits 55 sequences in PaperBLAST's database above the trusted cutoff. Showing hits to curated sequences only. Or see all hits or try another family.

YafA / b0239 fermentation-respiration switch protein from Escherichia coli K-12 substr. MG1655 (see 4 papers)
FRSA_ECOLI / P04335 Esterase FrsA; Fermentation/respiration switch protein; EC 3.1.1.1 from Escherichia coli (strain K12) (see 2 papers)
P04335 carboxylesterase (EC 3.1.1.1) from Escherichia coli (see paper)
Aligns to 1:414 / 414 (100.0%), covers 100.0% of PF06500, 780.2 bits

• function: Catalyzes the hydrolysis of esters (PubMed:15808744). Displays esterase activity toward pNP-butyrate (PubMed:15808744). May stimulate mixed-acid fermentation by acting as a fermentation/respiration switch that down-regulates respiration and up- regulates fermentation rates (PubMed:15169777).
  catalytic activity: a carboxylic ester + H2O = a carboxylate + an alcohol + H(+) (RHEA:21164)
  subunit: Forms a 1:1 complex specifically with the unphosphorylated form of the EIIA component of the glucose-specific PTS system (IIAGlc).
  disruption phenotype: Deletion of the gene increases cell respiration rate on several sugars including glucose.

FRSA_VIBVU / Q8DF91 Esterase FrsA; EC 3.1.1.1 from Vibrio vulnificus (strain CMCP6) (see 3 papers)
Aligns to 4:414 / 415 (99.0%), covers 99.5% of PF06500, 698.5 bits

• function: Catalyzes the hydrolysis of esters (PubMed:30951551). In vitro, prefers short chain alkanoate ester as substrate. Displays highest activity towards p-nitrophenyl acetate (pNPA). Has weaker activity towards p-nitrophenyl butyrate (pNPB) (PubMed:30951551).
  catalytic activity: a carboxylic ester + H2O = a carboxylate + an alcohol + H(+) (RHEA:21164)
  subunit: Monomer in solution (PubMed:21623357). Homodimer (PubMed:30951551). Forms a 1:1 complex with the unphosphorylated form of the EIIA component of the glucose-specific PTS system (IIAGlc) (PubMed:21623357).

LUC6_FUSSX / A0A6J4B4M6 Hydrolase LUC6; Lucilactaene biosynthesis cluster protein 6; EC 3.7.1.- from Fusarium sp. (see 2 papers)
Aligns to 39:274 / 419 (56.3%), covers 48.3% of PF06500, 49.7 bits

• function: Hydrolase; part of the gene cluster that mediates the biosynthesis of the mycotoxin lucilactaene and the lucilactaene-related compound NG-391 that act as cell cycle inhibitors with potent growth inhibitory activity against malarial parasites, moderate growth inhibitory activity against cancer cells, and no activity against bacteria and fungi (PubMed:32043422, PubMed:35484225). Within the pathway, LUC6 may catalyze the 2-pyrrolidone ring formation to form prelucilactaene C from prelucilactaene B, followed by C-15 hydroxylation by the same enzyme to give prelucilactaene D, epoxydation to yield prelucilactaene E, and finally cyclization to yield prelucilactaene F (Probable). The pathway begins with the hybrid PKS- NRPS synthetase LUC5 which is responsible for the condensation of one acetyl-coenzyme A (CoA) unit with six malonyl-CoA units and the amide linkage of the arising heptaketide and homoserine, subsequently releasing the first intermediate prelucilactaene B. Both the cytochrome P450 monooxygenase LUC2 and the hydrolase LUC6 function in parallel in modification of prelucilactaene B. LUC6 may catalyze the 2-pyrrolidone ring formation to form prelucilactaene C from prelucilactaene B, followed by C-15 hydroxylation by the same enzyme to give prelucilactaene D, which is then converted to prelucilactaene E by epoxidation, and finally to prelucilactaene F by cyclization. Prelucilactane D, prelucilactaene E, and prelucilactaene F can be converted to dihydrolucilactaene, NG391, and lucilactaene, respectively, via C-20 methyl group hydroxylation by the cytochrome P450 monooxygenase LUC2. However, LUC2, unlike FUS8 in fusarin C biosynthesis, is not enough for the full oxidation of the C-20 methyl group into carboxylic acid, which is a prerequisite for the final methylation step. The aldehyde dehydrogenase LUC3 is involved in the biosynthesis by further oxidation of the C-20 alcoholic analog prelucilactaene G into a carboxylic derivative. This unidentified carboxylic derivative may be converted to demethyllucilactaene. As the last step, the methyltransferase LUC1 methylates the hydroxyl group at C-21 of demethyllucilactaene to generate lucilactaene (Probable).

AYG1_ASPFU / Q4WZB3 Heptaketide hydrolyase ayg1; Conidial pigment biosynthesis protein ayg1; EC 3.7.1.- from Aspergillus fumigatus (strain ATCC MYA-4609 / CBS 101355 / FGSC A1100 / Af293) (Neosartorya fumigata) (see 12 papers)
Aligns to 71:399 / 406 (81.0%), covers 73.2% of PF06500, 43.7 bits

• function: Heptaketide hydrolyase; part of the gene cluster that mediates the biosynthesis of dihydroxynaphthalene (DHN)-melanin, a bluish-green pigment and a structural component of the conidial wall (PubMed:10515939, PubMed:11350964, PubMed:15310761, PubMed:19156203). The first step of the pathway is the production of the heptaketide naphtopyrone YWA1 by the polyketide synthase alb1 though condensation of acetyl-CoA with malonyl-CoA (PubMed:10515939). The naphtopyrone YWA1 is then converted to the pentaketide 1,3,6,8-tetrahydroxynaphthalene (1,3,6,8-THN) by the heptaketide hydrolyase ayp1 though chain-length shortening (PubMed:10515939, PubMed:11350964). 1,3,6,8-THN is substrate of the hydroxynaphthalene reductase arp2 to yield scytalone (PubMed:10515939, PubMed:11350964, PubMed:15310761). The scytalone dehydratase arp1 then reduces scytalone to 1,3,8-THN (PubMed:10515939). 1,3,8-THN is also substrate of the hydroxynaphthalene reductase arp2 to yield vermelone (PubMed:10515939). Vermelone is further converted by the multicopper oxidase abr1 to 1,8-DHN (PubMed:10515939). Finally the laccase abr2 transforms 1,8-DHN to DHN-melanin (PubMed:10515939). DHN- melanin biosynthesis appears to be initiated in endosomes where early enzymes (abl1, ayg1, arp1 and arp2) localize, with exocytosis leading to melanin deposition on the cell surface where late enzymes (abr1 and abr2) localize (PubMed:26972005). DHN-melanin is an important structural component of the outer cell wall and is required for the presence of conidial surface hydrophobins (PubMed:19703288). DHN- melanin also plays a crucial role in fungal virulence, including a protective role against the host's immune defenses (PubMed:19156203, PubMed:20145078, PubMed:21501368, PubMed:21747802, PubMed:21573171, PubMed:24818666). DHN-melanin protects also conidia against amoeba predation (PubMed:25684622).
  subunit: Homodimer.
  disruption phenotype: Leads to a yellow-green color of conidia (PubMed:11350964, PubMed:26972005). Impairs the accumulation of 1,3,6,8-tetrahydroxynaphthalene (1,3,6,8-THN) (PubMed:11350964). Results in an altered conidial surface with masked surface rodlet layer, leaky cell wall allowing the deposition of proteins on the cell surface and exposing the otherwise-masked cell wall polysaccharides at the surface (PubMed:24818666). Decreases the protection against the host's immune defenses (PubMed:21501368). Causes enhanced insect mortality compared to the parent strain in a wax moth Galleria mellonella infection model, probably through exacerbated immune response of the wax moth (PubMed:19156203).

Q93NG6 2,6-dihydroxypseudooxynicotine hydrolase (EC 3.7.1.19) from Paenarthrobacter nicotinovorans (see 3 papers)
DHPON_PAENI / Q93NG6 2,6-dihydropseudooxynicotine hydrolase; EC 3.7.1.19 from Paenarthrobacter nicotinovorans (Arthrobacter nicotinovorans) (see 3 papers)
Q93NG6 2,6-dihydroxypseudooxynicotine hydrolase (EC 3.7.1.19) from Paenarthrobacter nicotinovorans (see paper)
Aligns to 28:245 / 367 (59.4%), covers 48.8% of PF06500, 43.1 bits

• function: L-nicotine is used as a growth substrate. Plays a role in nicotine catabolism by cleaving a C-C bond in 2,6- dihydroxypseudooxynicotine.
  catalytic activity: 2,6-dihydroxypseudooxynicotine + H2O = 2,6-dihydroxypyridine + 4-(methylamino)butanoate + H(+) (RHEA:34167)
  subunit: Homodimer.

FUS2_GIBM7 / W7N6P0 20-hydroxy-prefusarin hydrolase FUS2; Fusarin biosynthesis protein 2; EC 3.7.1.- from Gibberella moniliformis (strain M3125 / FGSC 7600) (Maize ear and stalk rot fungus) (Fusarium verticillioides) (see 2 papers)
Aligns to 37:278 / 419 (57.8%), covers 49.0% of PF06500, 41.9 bits

• function: 20-hydroxy-prefusarin hydrolase; part of the gene cluster that mediates the biosynthesis of the mycotoxin fusarin C (PubMed:17121404, PubMed:22652150). Within the cluster, FUS1, FUS2, FUS8 and FUS9 are sufficient for fusarin production (By similarity). The roles of the other FUS members are yet undetermined (By similarity). The fusarin C synthetase FUS1 is responsible for the condensation of one acetyl-coenzyme A (CoA) unit with six malonyl-CoA units and the amide linkage of the arising heptaketide and homoserine, subsequently releasing the first intermediate, prefusarin, as an alcohol with an open ring structure (PubMed:17121404). The cytochrome P450 monooxygenase FUS8 participates in multiple oxidation processes at carbon C-20 and is able to use the FUS1 product as substrate, resulting in formation of 20-hydroxy-prefusarin (By similarity). This reaction seems to be essential before the 2-pyrrolidone ring closure can be catalyzed by FUS2, generating 20-hydroxy-fusarin (By similarity). FUS8 is able to further oxidizes carbon C-20 after ring closure, resulting in the formation of carboxy-fusarin C (By similarity). As the last step, FUS9 methylates the hydroxyl group at C-21 to generate fusarin C (By similarity). Fusarin C can then rearrange to epi-fusarin C, the (z)-isomers, and fusarin A and fusarin D (By similarity).

XENA_XENSI / A0A7L9F0X4 Alpha/beta hydrolase xenA; Xenoacremones biosynthesis cluster protein A; EC 3.7.1.- from Xenoacremonium sinensis (Endophyte fungus) (see paper)
Aligns to 15:283 / 425 (63.3%), covers 49.8% of PF06500, 41.7 bits

• function: Alpha/beta hydrolase; part of the gene cluster that mediates the biosynthesis of xenoacremones such as xenoacremone A, a compound that shows inhibitory activity toward the PI3K/AKT signaling pathway and which has the ability to induce apoptosis of A549 lung cancer cells (PubMed:34900544). Within the pathway, cooperation of the hybrid PKS- NRPS xenE and the trans-acting enoyl reductase xenG is responsible for the formation of the reduced tyrosine-nonaketide derivative (PubMed:34900544). The alpha/beta hydrolase xenA then accelerates intramolecular nucleophilic attack to give a pyrrolidone derivative (PubMed:34900544). Subsequently, three enzymes, xenF, xenD, and xenC, coordinately participate in the conversion to xenoacremone B (PubMed:34900544). XenF catalyzes sigmatropic rearrangement to form an A-ring, which leads to an unusual intermediate with a hexane ring, which is required for the formation of the tricarbocyclic product (PubMed:34900544). Epoxidation catalyzed by xenD and the formation of the paracyclophane ether catalyzed by xenC initiate a spontaneous intramolecular Diels-Alder (IMDA) reaction to yield xenoacremone B (PubMed:34900544). Spontaneous hydration of xenoacremone B leads to the formation of xenoacremone A, which undergoes subsequent methylation to afford xenoacremone C (PubMed:34900544).
  subunit: Homodimer.
  disruption phenotype: Does not affect the production of xenoacremones A and B but leads to the accumulation of 8.

Fus2 / S0EE80 fusarin oxygenase from Gibberella fujikuroi (strain CBS 195.34 / IMI 58289 / NRRL A-6831) (see 2 papers)
FUS2_GIBF5 / S0EE80 20-hydroxy-prefusarin hydrolase FUS2; Fusarin biosynthesis protein 2; EC 3.7.1.- from Gibberella fujikuroi (strain CBS 195.34 / IMI 58289 / NRRL A-6831) (Bakanae and foot rot disease fungus) (Fusarium fujikuroi) (see 2 papers)
Aligns to 38:274 / 419 (56.6%), covers 48.8% of PF06500, 40.9 bits

• function: 20-hydroxy-prefusarin hydrolase; part of the gene cluster that mediates the biosynthesis of the mycotoxin fusarin C (PubMed:23932525). Within the cluster, FUS1, FUS2, FUS8 and FUS9 are sufficient for fusarin production (PubMed:23932525). The roles of the other FUS members are yet undetermined (PubMed:23932525). The fusarin C synthetase FUS1 is responsible for the condensation of one acetyl- coenzyme A (CoA) unit with six malonyl-CoA units and the amide linkage of the arising heptaketide and homoserine, subsequently releasing the first intermediate, prefusarin, as an alcohol with an open ring structure (PubMed:23932525). The cytochrome P450 monooxygenase FUS8 participates in multiple oxidation processes at carbon C-20 and is able to use the FUS1 product as substrate, resulting in formation of 20- hydroxy-prefusarin (PubMed:23932525). This reaction seems to be essential before the 2-pyrrolidone ring closure can be catalyzed by FUS2, generating 20-hydroxy-fusarin (PubMed:23932525). FUS8 is able to further oxidizes carbon C-20 after ring closure, resulting in the formation of carboxy-fusarin C (PubMed:23932525). As the last step, FUS9 methylates the hydroxyl group at C-21 to generate fusarin C (PubMed:23932525). Fusarin C can then rearrange to epi-fusarin C, the (z)-isomers, and fusarin A and fusarin D (PubMed:23932525).
  disruption phenotype: Accumulates 20-hydroxy-prefusarin (PubMed:23932525).

PYDG_ACRSP / A0A8F4NUL3 Alpha/beta hydrolase pydG; Pyrrocidines biosynthesis cluster protein G; EC 3.7.1.- from Acremonium sp. (see paper)
Aligns to 40:280 / 426 (56.6%), covers 49.3% of PF06500, 37.6 bits

• function: Alpha/beta hydrolasee; part of the gene cluster that mediates the biosynthesis of pyrrocidines, fungal natural products containing a macrocyclic para-cyclophane connected to a decahydrofluorene ring system that show potent antibiotic activities toward Gram-negative bacteria (PubMed:33834778). Within the pathway, pydG catalyzes the Knoevenagel condensation that affords the 3-pyrrolin-2-one ring, using as substrate the polyketide-tyrosyl acyl thioester product of pydA (PubMed:33834778). The pathway begins with the PKS-NRPS pydA which, with the help of the trans-enoyl reductase pydC, synthesizes the polyketide-tyrosyl acyl thioester product which can be reductively off- loaded by the terminal reductase (R) domain in pydA. The alpha/beta hydrolase pydG is then required to catalyze the subsequent Knoevenagel condensation that affords the 3-pyrrolin-2-one ring, whereas the four proteins pydB, pydE, pydX and pydZ then function synergistically to form the cyclophane. PydB and the membrane-bound pydX and pydZ are lipid-binding proteins that can sequester and mold the pdyG product into the inverse S-shape. Binding of the medium chain reductase pydE to the complex would trigger the cascade oxidative cyclization. PydY is involved in the Diels-Alder cycloaddition that forms the decahydrofluorene core. Additional non-enzymatic hydroxylation yields pyrrocidine A2 which can be further reduced into pyrrocidine B by an endogenous reductase (Probable).
  subunit: Homodimer.

POXO_PENOX / A0A1W5T1Y7 Hydrolyase poxO; Oxaleimides biosynthesis cluster protein O; EC 3.7.1.- from Penicillium oxalicum (see paper)
Aligns to 43:272 / 421 (54.6%), covers 46.1% of PF06500, 37.0 bits

• function: Hydrolyase; part of the gene cluster that mediates the biosynthesis of oxaleimides, cytotoxic compounds containing an unusual disubstituted succinimide moiety (PubMed:28365998). The first step of the pathway is provided by the HR-PKS poxF that serves in a new mode of collaborative biosynthesis with the PKS-NRPS poxE, by providing the olefin containing amino acid substrate via the synthesis of an ACP- bound dec-4-enoate (PubMed:28365998). The cytochrome P450 monooxygenase poxM-catalyzed oxidation at the alpha-position creates the enzyme-bound 2-hydroxydec-4-enoyl-ACP thioester, which may be prone to spontaneous hydrolysis to yield 2-hydroxydec-4-enoic acid due to increased electrophilicity of the carbonyl (PubMed:28365998). 2-hydroxydec-4- enoic acid can then be further oxidized by poxM to yield the alpha- ketoacid 2-oxodec-4-enoicacid, which is reductively aminated by the aminotransferase poxL to yield (S,E)-2-aminodec-4-enoic acid (PubMed:28365998). The Hybrid PKS-NRPS synthetase poxE then performs condensation between the octaketide product of its PKS modules and the amino group of (S,E)-2-aminodec-4-enoic acid which is activated and incorporated by the adenylation domain (PubMed:28365998). The resulting aminoacyl product can be cyclized by the Diels-Alderase PoxQ and reductively released by the reductive (R) domain of poxE to yield an aldehyde intermediate (PubMed:28365998) (Probable). The released aldehyde is then substrate for a Knoevenagel condensation by the hydrolyase poxO followed by an oxidation at the 5-position of the pyrrolidone ring (PubMed:28365998). The presence of the olefin from the amino acid building block allows for migration of the substituted allyl group to occur (PubMed:28365998). This allylic transposition reaction takes place in a conjugate addition, semipinacol-like fashion to yield a succinimide intermediate (PubMed:28365998). Iterative two-electron oxidations of the C7 methyl of the succinimide intermediate to the carboxylic acid can be catalyzed by one of two remaining cytochrome P450 monooxygenasess poxC or poxD to yield oxaleimide A (PubMed:28365998). Subsequent oxidation yields the maleimide scaffold oxaleimide I (PubMed:28365998). Both oxaleimide A and oxaleimide I can undergo oxidative modifications in the decalin ring to yield the series of products oxaleimides B to H (PubMed:28365998).
  subunit: Homodimer.
  disruption phenotype: Impairs the productin of oxaleimides and leads to the accumulation of a trans-decalin containing alcohol intermediate.

POXO_PENO1 / S8ASK9 Hydrolyase poxO; Oxaleimides biosynthesis cluster protein O; EC 3.7.1.- from Penicillium oxalicum (strain 114-2 / CGMCC 5302) (Penicillium decumbens) (see paper)
Aligns to 43:272 / 421 (54.6%), covers 46.1% of PF06500, 36.2 bits

• function: Hydrolyase; part of the gene cluster that mediates the biosynthesis of oxaleimides, cytotoxic compounds containing an unusual disubstituted succinimide moiety (PubMed:28365998). The first step of the pathway is provided by the HR-PKS poxF that serves in a new mode of collaborative biosynthesis with the PKS-NRPS poxE, by providing the olefin containing amino acid substrate via the synthesis of an ACP- bound dec-4-enoate (PubMed:28365998). The cytochrome P450 monooxygenase poxM-catalyzed oxidation at the alpha-position creates the enzyme-bound 2-hydroxydec-4-enoyl-ACP thioester, which may be prone to spontaneous hydrolysis to yield 2-hydroxydec-4-enoic acid due to increased electrophilicity of the carbonyl (PubMed:28365998). 2-hydroxydec-4- enoic acid can then be further oxidized by poxM to yield the alpha- ketoacid 2-oxodec-4-enoicacid, which is reductively aminated by the aminotransferase poxL to yield (S,E)-2-aminodec-4-enoic acid (PubMed:28365998). The Hybrid PKS-NRPS synthetase poxE then performs condensation between the octaketide product of its PKS modules and the amino group of (S,E)-2-aminodec-4-enoic acid which is activated and incorporated by the adenylation domain (PubMed:28365998). The resulting aminoacyl product can be cyclized by the Diels-Alderase PoxQ and reductively released by the reductive (R) domain of poxE to yield an aldehyde intermediate (PubMed:28365998) (Probable). The released aldehyde is then substrate for a Knoevenagel condensation by the hydrolyase poxO followed by an oxidation at the 5-position of the pyrrolidone ring (PubMed:28365998). The presence of the olefin from the amino acid building block allows for migration of the substituted allyl group to occur (PubMed:28365998). This allylic transposition reaction takes place in a conjugate addition, semipinacol-like fashion to yield a succinimide intermediate (PubMed:28365998). Iterative two-electron oxidations of the C7 methyl of the succinimide intermediate to the carboxylic acid can be catalyzed by one of two remaining cytochrome P450 monooxygenasess poxC or poxD to yield oxaleimide A (PubMed:28365998). Subsequent oxidation yields the maleimide scaffold oxaleimide I (PubMed:28365998). Both oxaleimide A and oxaleimide I can undergo oxidative modifications in the decalin ring to yield the series of products oxaleimides B to H (PubMed:28365998).
  subunit: Homodimer.
  disruption phenotype: Impairs the productin of oxaleimides and leads to the accumulation of a trans-decalin containing alcohol intermediate.

GKAG_PENCI / A0A8F4NU75 Alpha/beta hydrolase gkaG; GKK1032 biosynthesis cluster protein G; EC 3.7.1.- from Penicillium citrinum (see paper)
Aligns to 35:282 / 427 (58.1%), covers 49.0% of PF06500, 33.9 bits

• function: Alpha/beta hydrolase; part of the gene cluster that mediates the biosynthesis of GKK1032, fungal natural products containing a macrocyclic para-cyclophane connected to a decahydrofluorene ring system that show potent antitumor activities (PubMed:33834778). Within the pathway, gkaG catalyzes the Knoevenagel condensation that affords the 3-pyrrolin-2-one ring, using as substrate the polyketide-tyrosyl acyl thioester product of gkaA (PubMed:33834778). The pathway begins with the PKS-NRPS gkaA which, with the help of the trans-enoyl reductase gkaC, synthesizes the polyketide-tyrosyl acyl thioester product which can be reductively off-loaded by the terminal reductase (R) domain in gkaA. The alpha/beta hydrolase gkaG is then required to catalyze the subsequent Knoevenagel condensation that affords the 3- pyrrolin-2-one ring, whereas the three proteins gkaB, gkaX and gkaZ then function synergistically to form the cyclophane (Probable).
  subunit: Homodimer.

ACRC_ASPA1 / P9WEZ7 Hydrolase acrC; Acurin A biosynthesis cluster protein C; EC 3.7.1.- from Aspergillus aculeatus (strain ATCC 16872 / CBS 172.66 / WB 5094) (see paper)
Aligns to 40:315 / 428 (64.5%), covers 47.1% of PF06500, 30.4 bits

• function: Hydrolase; part of the cluster that mediates the biosynthesis of acurin A, a highly reduced polyketide coupled to a serine via a peptide bond (PubMed:32234543). The activities of the highly reducing polyketide synthase acrA and the nonribosomal peptide synthetase acrB are collectively responsible for the synthesis of the acurin A core structure with a heptaketide backbone produced by acrA covalently fused to a L-serine by acrB (PubMed:32234543). After the formation of the PK- NRP hybrid product, it is detached from acrB by reductive release to set up the formation of the lactam ring by aldol condensation (Probable). The hydrolyase acrC then catalyzes water loss to generate a double bond in the ring (Probable). This double bond is probably reduced, which is followed by three oxidations at C-22 to generate the carboxylic acid moiety, involving probably the FAD-binding monooxygenase acrE and the cytochrome P450 monooxygenases acrD and acrF (Probable). Finally, a last methylation step performed by the O- methyltransferase acrG leads to the production of acurin A (Probable).
  disruption phenotype: Abolishes the production of acurin A.

UCSC_ACRSP / A0A411KUP9 Alpha/beta hydrolase ucsC; UCS1025A pyrrolizidinone biosynthesis cluster protein C; EC 3.7.1.- from Acremonium sp. (see paper)
Aligns to 38:298 / 492 (53.0%), covers 49.0% of PF06500, 26.5 bits

• function: Alpha/beta hydrolase; part of the gene cluster that mediates the biosynthesis of UCS1025A, a member of the pyrrolizidinone family that acts as a strong telomerase inhibitor and displays potent antibacterial and antitumor properties (PubMed:29373009). These compounds share a hemiaminal-containing pyrrolizidinone core fused with a gamma-lactone, giving a furopyrrolizidine that is connected to a decalin fragment (PubMed:29373009). The polyketide synthase module (PKS) of the PKS-NRPS ucsA is responsible for the synthesis of the polyketide backbone via the condensation of an acetyl-CoA starter unit with 6 malonyl-CoA units (PubMed:29373009). The downstream nonribosomal peptide synthetase (NRPS) module then amidates the carboxyl end of the polyketide with a 2S,3S-methylproline derived from L-isoleucine by the 2-oxoglutarate-dependent dioxygenase ucsF which converts L-isoleucine to (4S,5S)-4-methylpyrroline-5-carboxylate that is further converted to 2S,3S-methylproline by the pyrroline-5-carboxylate reductase ucsG (PubMed:29373009). Reductive release of the completed aminoacyl polyketide from the assembly line can form the 3-pyrrolin-2-one structure via an intramolecular Knoevenagel reaction (PubMed:29373009). Because ucsA lacks a designated enoylreductase (ER) domain, the required activity is provided the enoyl reductase ucsL (PubMed:29373009). This keto acyclic precursor is the substrate of the Diels-Alderase ucsH, that catalyzes the Diels-Alder cycloaddition (PubMed:29373009). Oxidation of the 3S-methyl group to a carboxylate by the cytochrome P450 monooxygenase ucsK allows an oxa-Michael cyclization that might involve the reductase/dehydrogenase ucsI and which furnishes the furopyrrolizidine (PubMed:29373009). The oxidase ucsJ likely plays a critical role in stereoselective reduction of the C5-C6 double bond to afford the required R-configured carboxylate group (Probable). Further enolization and oxidation at C5 by an unidentified enzyme affords the last intermediate that can undergo oxa-Michael cyclization to yield UCS1025A (Probable).
  subunit: Homodimer.

ORFZB_PYRO7 / G4MVZ4 Hydrolase ORFZ; ACE1 cytochalasan biosynthesis cluster protein ORFZ; EC 3.7.1.- from Pyricularia oryzae (strain 70-15 / ATCC MYA-4617 / FGSC 8958) (Rice blast fungus) (Magnaporthe oryzae) (see 3 papers)
Aligns to 27:351 / 424 (76.7%), covers 47.6% of PF06500, 25.5 bits

• function: Hydrolyase; part of the gene cluster that mediates the biosynthesis of a tyrosine-derived cytochalasan acting as a fungal signal recognized by resistant rice plants and leads to avirulence in Pi33 resistant rice cultivars (PubMed:18433432). The first step in the pathway is catalyzed by the hybrid PKS-NRPS ACE1, assisted by the enoyl reductase RAP1, that are responsible for fusion of the tyrosine precursor and the polyketide backbone (PubMed:29142718). The polyketide synthase module (PKS) of ACE1 is responsible for the synthesis of the polyketide backbone and the downstream nonribosomal peptide synthetase (NRPS) amidates the carboxyl end of the polyketide with the tyrosine precursor (PubMed:29142718). Because ACE1 lacks a designated enoylreductase (ER) domain, the required activity is provided the enoyl reductase RAP1 (PubMed:29142718). Reduction by the hydrolyase ORFZ, followed by dehydration and intra-molecular Diels-Alder cyclization by the Diels-Alderase ORF3 then yield the required isoindolone-fused macrocycle (Probable). A number of oxidative steps catalyzed by the tailoring enzymes identified within the cluster, including cytochrome P450 monooxygenases CYP1 to CYP4, the FAD-linked oxidoreductase OXR2 and the short-chain dehydrogenase/reductase OXR1, are further required to afford the final cytochalasans that confer avirulence and which have still to be identified (Probable). The monooxygenase CYP1 has been shown to be a site-selective C-18 hydroxylase whereas the function of CYP3 is the site-selective epoxidation of the C-6/C-7 olefin that is present in some intermediate compounds (PubMed:31644300). Finally, SYN2 and RAP2 are not required for avirulence in Pi33 resistant rice cultivars (PubMed:18433432).
  subunit: Homodimer.

GRGF_PENSQ / A0A6F8RQ06 Polyketide transferase grgF; Gregatin A biosynthesis cluster protein F; Hydrolase grgF; EC 2.3.-.- from Penicillium sp. (see paper)
Aligns to 2:171 / 294 (57.8%), covers 37.9% of PF06500, 24.9 bits

• function: Polyketide transferase; part of the gene cluster that mediates the biosynthesis of gregatin A, a fungal polyketide featuring an alkylated furanone core (PubMed:32275405). The PKS grgA synthesizes C11 and C4 polyketide chains in the presence and absence of the trans- enoyl reductase grgB, respectively (PubMed:32275405). The polyketide transferase grgF is then responsible for the fusion of the two carbon chains to produce the furanone skeleton of gregatin A (PubMed:32275405). GrgF first undergoes a conformational change to an open form, and the active site Cys-115 is acylated by the C11 chain. After the elimination of the phosphopantetheinyl chain, the second polyketide chain of four carbons long is delivered adjacent to the enzyme-bound C11 chain. The catalytic histidine, His-269, deprotonates a proton from C-2 of the long chain, and the resultant carbanion attacks the C-1 carbonyl of the crotonyl group to perform Claisen condensation, by which the phosphopantetheinyl chain is released. Eventually, hydrolysis of the thioester linkage probably by a His-269- activated water molecule completes the reaction to afford the grgF final product (PubMed:32275405). Next, the cytochrome P450 monooxygenase grgG accepts the unstable grgF final product as substrate and performs the oxidative cyclization to furnish the gregatin scaffold and leads to the formation of desmethylgregatin A (PubMed:32275405). Finally, the O-methyltransferase grgD methylates the carboxyl group of desmethylgregatin A to provide gregatin A (PubMed:32275405).
  subunit: Homodimer.

CLAH_PENCR / A0A481WQ01 Polyketide transferase claH; Clavatol biosynthesis cluster protein H; EC 2.3.-.- from Penicillium crustosum (Blue mold fungus) (see 2 papers)
Aligns to 3:165 / 308 (52.9%), covers 32.1% of PF06500, 24.2 bits

• function: Polyketide transferase; part of the cla gene cluster that produces clavatol and ortho-quinone methide (PubMed:30811183). The clavatol biosynthesis cluster cla and the terrestric acid cluster tra are both involved in the production of peniphenones and penilactones (PubMed:30811183). The non-reducing PKS claF is responsible for the formation of clavatol from successive condensations of 3 malonyl-CoA units, presumably with a simple acetyl-CoA starter unit, and 2 methylation steps (PubMed:30811183). The esterase claE probably collaborates with claF by catalyzing the hydrolysis of ACP-bound acyl intermediates to free the ACP from stalled intermediates (By similarity). The clavatol oxidase claD then converts clavatol to hydroxyclavatol (PubMed:30811183). Spontaneous dehydration of hydroxyclavatol leads to the accumulation of the highly active ortho- quinone methide (PubMed:30811183, PubMed:31860310). On the other hand, the PKS-NRPS hybrid traA is involved in the formation of crustosic acid, with the help of traB and traD (PubMed:30811183). The polyketide synthase module (PKS) of traA is responsible for the synthesis of the polyketide backbone via the condensation of an acetyl-CoA starter unit with 3 malonyl-CoA units (PubMed:30811183). The downstream nonribosomal peptide synthetase (NRPS) module then amidates the carboxyl end of the polyketide with L-malic acid (PubMed:30811183). Because traA lacks a designated enoylreductase (ER) domain, the required activity is provided the enoyl reductase traG (By similarity). Crustosic acid undergoes decarboxylation and isomerization to the terrestric acid, catalyzed by the 2-oxoglutarate-dependent dioxygenase traH (PubMed:30811183). Both acids are further converted to the 2 gamma- butyrolactones (R)-5-methyltetronic acid and (S)-5- carboxylmethyltetronic acid, with involvement of the cytochrome P450 monooxygenase claJ (PubMed:30811183). Spontaneous addition of the methide to these gamma-butyrolactones leads to peniphenone D and penilactone D, which undergo again stereospecific attacking by methide to give penilactones A and B (PubMed:30811183, PubMed:31860310). The function of the polyketide transferase claH has not been investigated yet (Probable).

PSOB_ASPFU / Q4WAZ8 Alpha/beta hydrolase psoB; Pseurotin biosynthesis protein B; EC 3.7.1.- from Aspergillus fumigatus (strain ATCC MYA-4609 / CBS 101355 / FGSC A1100 / Af293) (Neosartorya fumigata) (see 3 papers)
Aligns to 56:272 / 445 (48.8%), covers 33.8% of PF06500, 23.6 bits

• function: Alpha/beta hydrolase; part of the gene cluster that mediates the biosynthesis of pseurotin A, a competitive inhibitor of chitin synthase and an inducer of nerve-cell proliferation (PubMed:24082142, PubMed:24939566). The PKS-NRPS hybrid synthetase psoA is responsible for the biosynthesis of azaspirene, one of the first intermediates having the 1-oxa-7-azaspiro[4,4]-non-2-ene-4,6-dione core of pseurotin, via condensation of one acetyl-CoA, 4 malonyl-CoA, and a L- phenylalanine molecule (PubMed:24082142, PubMed:24939566). The dual- functional monooxygenase/methyltransferase psoF seems to be involved in the addition of the C3 methyl group onto the pseurotin scaffold (PubMed:24939566). Azaspirene is then converted to synerazol through 4 steps including oxidation of C17 by the cytochrome P450 monooxygenase psoD, O-methylation of the hydroxy group of C8 by the methyltransferase psoC, and the trans-to-cis isomerization of the C13 olefin by the glutathione S-transferase psoE (PubMed:24939566). The fourth step of synerazol production is performed by the dual-functional monooxygenase/methyltransferase psoF which seems to catalyze the epoxidation of the intermediate deepoxy-synerazol (PubMed:24939566). Synerazol can be attacked by a water molecule nonenzymatically at two different positions to yield two diol products, pseurotin A and pseurotin D (PubMed:24939566).
  subunit: Homodimer.
  disruption phenotype: Results in significant reduction of pseurotin production (PubMed:24082142).

FUJ3_GIBF5 / S0EBV2 Polyketide transferase FFUJ_12241; Fujikurins biosynthesis cluster protein FFUJ_12241; EC 2.3.-.- from Gibberella fujikuroi (strain CBS 195.34 / IMI 58289 / NRRL A-6831) (Bakanae and foot rot disease fungus) (Fusarium fujikuroi) (see 2 papers)
Aligns to 5:130 / 320 (39.4%), covers 28.3% of PF06500, 23.1 bits

• function: Polyketide transferase; part of the gene cluster that mediates the biosynthesis of fujikurins A-D, secondary metabolites playing a role during rice infection (PubMed:23825955, PubMed:26192387). The polyketide synthase PKS19 acts with the trans- enoyl reductase FFUJ_12240 and the polyketide transferase FFUJ_12241 to produce fujikurins, however, the biosynthesis pathway has not been identified yet (PubMed:23825955, PubMed:26192387).

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