Adenylate forming domain, Class I superfamily; This family includes acyl- and aryl-CoA ligases, as well as the adenylation domain of nonribosomal peptide synthetases and firefly luciferases. The adenylate-forming enzymes catalyze an ATP-dependent two-step reaction to first activate a carboxylate substrate as an adenylate and then transfer the carboxylate to the pantetheine group of either coenzyme A or an acyl-carrier protein. The active site of the domain is located at the interface of a large N-terminal subdomain and a smaller C-terminal subdomain.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 488471904   7 VENVIVVRNTKTEVSMDLTCDHWYDELCKLpiAKGKCETVQVVSEDPLFILYTSGSTGKPKAIVHTHGGYQVGTYITLKQ 86
Cdd:cd05966  189 VEKVLVVKRTGGEVPMTEGRDLWWHDLMAK--QSPECEPEWMDSEDPLFILYTSGSTGKPKGVVHTTGGYLLYAATTFKY 266

                         90       100
                 ....*....|....*....|
gi 488471904  87 CFDIKEEDRWWCTADPGWIT 106
Cdd:cd05966  267 VFDYHPDDIYWCTADIGWIT 286

Acetyl-CoA synthetase (also known as acetate-CoA ligase and acetyl-activating enzyme); Acetyl-CoA synthetase (ACS, EC 6.2.1.1, acetate#CoA ligase or acetate:CoA ligase (AMP-forming)) catalyzes the formation of acetyl-CoA from acetate, CoA, and ATP. Synthesis of acetyl-CoA is carried out in a two-step reaction. In the first step, the enzyme catalyzes the synthesis of acetyl-AMP intermediate from acetate and ATP. In the second step, acetyl-AMP reacts with CoA to produce acetyl-CoA. This enzyme is widely present in all living organisms. The activity of this enzyme is crucial for maintaining the required levels of acetyl-CoA, a key intermediate in many important biosynthetic and catabolic processes. Acetyl-CoA is used in the biosynthesis of glucose, fatty acids, and cholesterol. It can also be used in the production of energy in the citric acid cycle. Eukaryotes typically have two isoforms of acetyl-CoA synthetase, a cytosolic form involved in biosynthetic processes and a mitochondrial form primarily involved in energy generation.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 488471904   7 VENVIVVRNTKTEVSMDLTCDHWYDELCKLpiAKGKCETVQVVSEDPLFILYTSGSTGKPKAIVHTHGGYQVGTYITLKQ 86
Cdd:cd05966  189 VEKVLVVKRTGGEVPMTEGRDLWWHDLMAK--QSPECEPEWMDSEDPLFILYTSGSTGKPKGVVHTTGGYLLYAATTFKY 266

                         90       100
                 ....*....|....*....|
gi 488471904  87 CFDIKEEDRWWCTADPGWIT 106
Cdd:cd05966  267 VFDYHPDDIYWCTADIGWIT 286

Acyl-coenzyme A synthetase/AMP-(fatty) acid ligase [Lipid transport and metabolism];

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 488471904   7 VENVIVVRNTKTEVSMDLtcDHWYDELckLPIAKGKCETVQVVSEDPLFILYTSGSTGKPKAIVHTHGGYQVGTYITLKQ 86
Cdd:COG0365  144 LEHVIVVGRTGADVPMEG--DLDWDEL--LAAASAEFEPEPTDADDPLFILYTSGTTGKPKGVVHTHGGYLVHAATTAKY 219

                         90       100
                 ....*....|....*....|
gi 488471904  87 CFDIKEEDRWWCTADPGWIT 106
Cdd:COG0365  220 VLDLKPGDVFWCTADIGWAT 239

AMP-binding enzyme;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 488471904   16 TKTEVSMDLTCDHWYDELCKLPIAKGKCETVQVVSEDPLFILYTSGSTGKPKAIVHTHGG--YQVGTYITLKQC-FDIKE 92
Cdd:pfam00501 120 LVLVLDRDPVLKEEPLPEEAKPADVPPPPPPPPDPDDLAYIIYTSGTTGKPKGVMLTHRNlvANVLSIKRVRPRgFGLGP 199

                          90
                  ....*....|....
gi 488471904   93 EDRWWCTADPGWIT 106
Cdd:pfam00501 200 DDRVLSTLPLFHDF 213

Acetyl-CoA synthetase (also known as acetate-CoA ligase and acetyl-activating enzyme); Acetyl-CoA synthetase (ACS, EC 6.2.1.1, acetate#CoA ligase or acetate:CoA ligase (AMP-forming)) catalyzes the formation of acetyl-CoA from acetate, CoA, and ATP. Synthesis of acetyl-CoA is carried out in a two-step reaction. In the first step, the enzyme catalyzes the synthesis of acetyl-AMP intermediate from acetate and ATP. In the second step, acetyl-AMP reacts with CoA to produce acetyl-CoA. This enzyme is widely present in all living organisms. The activity of this enzyme is crucial for maintaining the required levels of acetyl-CoA, a key intermediate in many important biosynthetic and catabolic processes. Acetyl-CoA is used in the biosynthesis of glucose, fatty acids, and cholesterol. It can also be used in the production of energy in the citric acid cycle. Eukaryotes typically have two isoforms of acetyl-CoA synthetase, a cytosolic form involved in biosynthetic processes and a mitochondrial form primarily involved in energy generation.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 488471904   7 VENVIVVRNTKTEVSMDLTCDHWYDELCKLpiAKGKCETVQVVSEDPLFILYTSGSTGKPKAIVHTHGGYQVGTYITLKQ 86
Cdd:cd05966  189 VEKVLVVKRTGGEVPMTEGRDLWWHDLMAK--QSPECEPEWMDSEDPLFILYTSGSTGKPKGVVHTTGGYLLYAATTFKY 266

                         90       100
                 ....*....|....*....|
gi 488471904  87 CFDIKEEDRWWCTADPGWIT 106
Cdd:cd05966  267 VFDYHPDDIYWCTADIGWIT 286

Acyl-coenzyme A synthetase/AMP-(fatty) acid ligase [Lipid transport and metabolism];

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 488471904   7 VENVIVVRNTKTEVSMDLtcDHWYDELckLPIAKGKCETVQVVSEDPLFILYTSGSTGKPKAIVHTHGGYQVGTYITLKQ 86
Cdd:COG0365  144 LEHVIVVGRTGADVPMEG--DLDWDEL--LAAASAEFEPEPTDADDPLFILYTSGTTGKPKGVVHTHGGYLVHAATTAKY 219

                         90       100
                 ....*....|....*....|
gi 488471904  87 CFDIKEEDRWWCTADPGWIT 106
Cdd:COG0365  220 VLDLKPGDVFWCTADIGWAT 239

acetate-CoA ligase; This family includes acyl- and aryl-CoA ligases, as well as the adenylation domain of nonribosomal peptide synthetases and firefly luciferases. The adenylate-forming enzymes catalyze an ATP-dependent two-step reaction to first activate a carboxylate substrate as an adenylate and then transfer the carboxylate to the pantetheine group of either coenzyme A or an acyl-carrier protein. The active site of the domain is located at the interface of a large N-terminal subdomain and a smaller C-terminal subdomain.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 488471904   6 AVENVIVVRNTKTEVSMDLTCDHWYDELckLPIAKGKCETVQVVSEDPLFILYTSGSTGKPKAIVHTHGGYQVGTYITLK 85
Cdd:cd17634  189 SVEHVIVLKRTGSDIDWQEGRDLWWRDL--IAKASPEHQPEAMNAEDPLFILYTSGTTGKPKGVLHTTGGYLVYAATTMK 266

                         90       100
                 ....*....|....*....|....
gi 488471904  86 QCFDIKEEDRWWCTADPGWITDTP 109
Cdd:cd17634  267 YVFDYGPGDIYWCTADVGWVTGHS 290

Uncharacterized subfamily of Acetyl-CoA synthetase like family (ACS); This family is most similar to acetyl-CoA synthetase. Acetyl-CoA synthetase (ACS) catalyzes the formation of acetyl-CoA from acetate, CoA, and ATP. Synthesis of acetyl-CoA is carried out in a two-step reaction. In the first step, the enzyme catalyzes the synthesis of acetyl-AMP intermediate from acetate and ATP. In the second step, acetyl-AMP reacts with CoA to produce acetyl-CoA. This enzyme is only present in bacteria.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*...
gi 488471904  51 EDPLFILYTSGSTGKPKAIVHTHGGyQVGTYITLKQCFDIKEEDRWWCTADPGWITDT 108
Cdd:cd05969   89 EDPTLLHYTSGTTGTPKGVLHVHDA-MIFYYFTGKYVLDLHPDDIYWCTADPGWVTGT 145

Uncharacterized acyl-CoA synthetase subfamily similar to Acetoacetyl-CoA synthetase; This uncharacterized acyl-CoA synthetase family (EC 6.2.1.16, or acetoacetate#CoA ligase or acetoacetate:CoA ligase (AMP-forming)) is highly homologous to acetoacetyl-CoA synthetase. However, the proteins in this family exist in only bacteria and archaea. AACS is a cytosolic ligase that specifically activates acetoacetate to its coenzyme A ester by a two-step reaction. Acetoacetate first reacts with ATP to form an acyl-adenylate intermediate, which then reacts with CoA to produce an acyl-CoA ester. This is the first step of the mevalonate pathway of isoprenoid biosynthesis via isopentenyl diphosphate. Isoprenoids are a large class of compounds found in all living organisms.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 488471904   7 VENVIVVRNTKTEVSMDLTCDHWYDELCKLPIAkgkcETVQVVSEDPLFILYTSGSTGKPKAIVHTHGGYQVGTYITLKQ 86
Cdd:cd05968  196 VEKVVVVRHLGNDFTPAKGRDLSYDEEKETAGD----GAERTESEDPLMIIYTSGTTGKPKGTVHVHAGFPLKAAQDMYF 271

                         90       100
                 ....*....|....*....|
gi 488471904  87 CFDIKEEDR-WWCTaDPGWI 105
Cdd:cd05968  272 QFDLKPGDLlTWFT-DLGWM 290

Medium-chain acyl-CoA synthetase (MACS or ACSM); MACS catalyzes the two-step activation of medium chain fatty acids (containing 4-12 carbons). The carboxylate substrate first reacts with ATP to form an acyl-adenylate intermediate, which then reacts with CoA to produce an acyl-CoA ester. The acyl-CoA is a key intermediate in many important biosynthetic and catabolic processes.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 488471904  38 IAKGKCETVQVVSEDPLFILYTSGSTGKPKAIVHTHgGYQVGTYITLKQCFDIKEEDRWWCTADPGWIT 106
Cdd:cd05972   68 LEAAGAKAIVTDAEDPALIYFTSGTTGLPKGVLHTH-SYPLGHIPTAAYWLGLRPDDIHWNIADPGWAK 135

Acetoacetyl-CoA synthetase (acetoacetate-CoA ligase, AACS); AACS is a cytosolic ligase that specifically activates acetoacetate to its coenzyme A ester by a two-step reaction. Acetoacetate first reacts with ATP to form an acyl-adenylate intermediate, which then reacts with CoA to produce an acyl-CoA ester. This is the first step of the mevalonate pathway of isoprenoid biosynthesis via isopentenyl diphosphate. Isoprenoids are a large class of compounds found in all living organisms. AACS is widely distributed in bacteria, archaea and eukaryotes. In bacteria, AACS is known to exhibit an important role in the metabolism of poly-b-hydroxybutyrate, an intracellular reserve of organic carbon and chemical energy by some microorganisms. In mammals, AACS influences the rate of ketone body utilization for the formation of physiologically important fatty acids and cholesterol.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 488471904  10 VIVVRNTKTEVSMDLTCD---HWYDElCKLPIAKGKCETVQVVSEDPLFILYTSGSTGKPKAIVHTHGGyqvgtyiTLKQ 86
Cdd:cd05943  206 VVVVPYTVAAGQPDLSKIakaLTLED-FLATGAAGELEFEPLPFDHPLYILYSSGTTGLPKCIVHGAGG-------TLLQ 277

                         90       100
                 ....*....|....*....|....*.
gi 488471904  87 -------CFDIKEEDRWWCTADPGWI 105
Cdd:cd05943  278 hlkehilHCDLRPGDRLFYYTTCGWM 303

Adenylate forming domain, Class I, also known as the ANL superfamily; This family is known as the ANL (acyl-CoA synthetases, the NRPS adenylation domains, and the Luciferase enzymes) superfamily. It includes acyl- and aryl-CoA ligases, as well as the adenylation domain of nonribosomal peptide synthetases and firefly luciferases.The adenylate-forming enzymes catalyze an ATP-dependent two-step reaction to first activate a carboxylate substrate as an adenylate and then transfer the carboxylate to the pantetheine group of either coenzyme A or an acyl-carrier protein. The active site of the domain is located at the interface of a large N-terminal subdomain and a smaller C-terminal subdomain.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....
gi 488471904  52 DPLFILYTSGSTGKPKAIVHTHGGYqVGTYITLKQCFDIKEEDRWWCTADPGWI 105
Cdd:cd04433    1 DPALILYTSGTTGKPKGVVLSHRNL-LAAAAALAASGGLTEGDVFLSTLPLFHI 53

propionyl-CoA synthetase; Provisional

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*.
gi 488471904  50 SEDPLFILYTSGSTGKPKAIVHTHGGYQVGTYITLKQCFDIKEEDRWWCTADPGWI 105
Cdd:PRK10524 232 SNEPSYILYTSGTTGKPKGVQRDTGGYAVALATSMDTIFGGKAGETFFCASDIGWV 287

Uncharacterized subfamily of medium-chain acyl-CoA synthetase (MACS); MACS catalyzes the two-step activation of medium chain fatty acids (containing 4-12 carbons). The carboxylate substrate first reacts with ATP to form an acyl-adenylate intermediate, which then reacts with CoA to produce an acyl-CoA ester. MACS enzymes are localized to mitochondria.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*....
gi 488471904  50 SEDPLFILYTSGSTGKPKAIVHTHG---GYQVGTYITLkQCFDiKEEDRWWCTADPGWI 105
Cdd:cd05971   87 SDDPALIIYTSGTTGPPKGALHAHRvllGHLPGVQFPF-NLFP-RDGDLYWTPADWAWI 143

amino acid adenylation domain; This model represents a domain responsible for the specific recognition of amino acids and activation as adenylyl amino acids. The reaction catalyzed is aa + ATP -> aa-AMP + PPi. These domains are usually found as components of multi-domain non-ribosomal peptide synthetases and are usually called "A-domains" in that context. A-domains are almost invariably followed by "T-domains" (thiolation domains, pfam00550) to which the amino acid adenylate is transferred as a thiol-ester to a bound pantetheine cofactor with the release of AMP (these are also called peptide carrier proteins, or PCPs. When the A-domain does not represent the first module (corresponding to the first amino acid in the product molecule) it is usually preceded by a "C-domain" (condensation domain, pfam00668) which catalyzes the ligation of two amino acid thiol-esters from neighboring modules. This domain is a subset of the AMP-binding domain found in Pfam (pfam00501) which also hits substrate--CoA ligases and luciferases. Sequences scoring in between trusted and noise for this model may be ambiguous as to whether they activate amino acids or other molecules lacking an alpha amino group.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*...
gi 488471904   50 SEDPLFILYTSGSTGKPKAIVHTHGGyqVGTYIT-LKQCFDIKEEDRW 96
Cdd:TIGR01733 119 PDDLAYVIYTSGSTGRPKGVVVTHRS--LVNLLAwLARRYGLDPDDRV 164

Benzoate CoA ligase (BCL) and similar adenylate forming enzymes; This family contains benzoate CoA ligase (BCL) and related ligases that catalyze the acylation of benzoate derivatives, 2-aminobenzoate and 4-hydroxybenzoate. Aromatic compounds represent the second most abundant class of organic carbon compounds after carbohydrates. Xenobiotic aromatic compounds are also a major class of man-made pollutants. Some bacteria use benzoate as the sole source of carbon and energy through benzoate degradation. Benzoate degradation starts with its activation to benzoyl-CoA by benzoate CoA ligase. The reaction catalyzed by benzoate CoA ligase proceeds via a two-step process; the first ATP-dependent step forms an acyl-AMP intermediate, and the second step forms the acyl-CoA ester with release of the AMP.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 488471904  38 IAKGKCETVQVVSEDPLFILYTSGSTGKPKAIVHTHGGYQVGTYITLKQCFDIKEEDRWWCTA 100
Cdd:cd05919   78 ARDCEARLVVTSADDIAYLLYSSGTTGPPKGVMHAHRDPLLFADAMAREALGLTPGDRVFSSA 140

fatty acyl-CoA synthetase, including FadD13; This family contains fatty acyl-CoA synthetases, including Mycobacterium tuberculosis acid-induced operon MymA encoding the fatty acyl-CoA synthetase FadD13 which is essential for virulence and intracellular growth of the pathogen. The fatty acyl-CoA synthetase activates lipids before entering into the metabolic pathways and is also involved in transmembrane lipid transport. However, unlike soluble fatty acyl-CoA synthetases, but like the mammalian integral-membrane very-long-chain acyl-CoA synthetases, FadD13 accepts lipid substrates up to the maximum length of C26, and this is facilitated by an extensive hydrophobic tunnel from the active site to a positively charged patch. Also included is feruloyl-CoA synthetase (Fcs) in Rhodococcus strains where it is involved in biotechnological vanillin production from eugenol and ferulic acid via a non-beta-oxidative pathway.

                         10        20
                 ....*....|....*....|....*..
gi 488471904  48 VVSEDPLFILYTSGSTGKPKAIVHTHG 74
Cdd:cd17631   95 VLFDDLALLMYTSGTTGRPKGAMLTHR 121

Uncharacterized subfamily of medium-chain acyl-CoA synthetase (MACS); MACS catalyzes the two-step activation of medium chain fatty acids (containing 4-12 carbons). The carboxylate substrate first reacts with ATP to form an acyl-adenylate intermediate, which then reacts with CoA to produce an acyl-CoA ester. MACS enzymes are localized to mitochondria.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*
gi 488471904  50 SEDPLFILYTSGSTGKPKAIVHTHGGYQVGTYITLkQCFDIKEEDRWWCTADPGW 104
Cdd:cd05974   84 ADDPMLLYFTSGTTSKPKLVEHTHRSYPVGHLSTM-YWIGLKPGDVHWNISSPGW 137

Prokaryotic long-chain fatty acid CoA synthetases similar to Escherichia coli FadD; This subfamily of the AMP-forming adenylation family contains Escherichia coli FadD and similar prokaryotic fatty acid CoA synthetases. FadD was characterized as a long-chain fatty acid CoA synthetase. The gene fadD is regulated by the fatty acid regulatory protein FadR. Fatty acid CoA synthetase catalyzes the formation of fatty acyl-CoA in a two-step reaction: the formation of a fatty acyl-AMP molecule as an intermediate, followed by the formation of a fatty acyl-CoA. This is a required step before free fatty acids can participate in most catabolic and anabolic reactions.

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|....*....
gi 488471904  26 CDHWYDELCKLPIAKGkcETVQVVSEDPLFILYTSGSTGKPKAIVHTHG 74
Cdd:cd05936  102 VAVSFTDLLAAGAPLG--ERVALTPEDVAVLQYTSGTTGVPKGAMLTHR 148

C-terminal domain of the acyl-acyl carrier protein synthetase (also called 2-acylglycerophosphoethanolamine acyltransferase, Aas); Acyl-acyl carrier protein synthase (Aas) is a membrane protein responsible for a minor pathway of incorporating exogenous fatty acids into membrane phospholipids. Its in vitro activity is characterized by the ligation of free fatty acids between 8 and 18 carbons in length to the acyl carrier protein sulfydryl group (ACP-SH) in the presence of ATP and Mg2+. However, its in vivo function is as a 2-acylglycerophosphoethanolamine (2-acyl-GPE) acyltransferase. The reaction occurs in two steps: the acyl chain is first esterified to acyl carrier protein (ACP) via a thioester bond, followed by a second step where the acyl chain is transferred to a 2-acyllysophospholipid, thus completing the transacylation reaction. This model represents the C-terminal domain of the enzyme, which belongs to the class I adenylate-forming enzyme family, including acyl-CoA synthetases.

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|....*.
gi 488471904  50 SEDPLFILYTSGSTGKPKAIVHTHGGYQVGTYiTLKQCFDIKEEDR 95
Cdd:cd05909  146 PDDPAVILFTSGSEGLPKGVVLSHKNLLANVE-QITAIFDPNPEDV 190

The adenylation domain of nonribosomal peptide synthetases (NRPS), including salinosporamide A polyketide synthase; The adenylation (A) domain of NRPS recognizes a specific amino acid or hydroxy acid and activates it as an (amino) acyl adenylate by hydrolysis of ATP. The activated acyl moiety then forms a thioester to the enzyme-bound cofactor phosphopantetheine of a peptidyl carrier protein domain. NRPSs are large multifunctional enzymes which synthesize many therapeutically useful peptides in bacteria and fungi via a template-directed, nucleic acid independent nonribosomal mechanism. These natural products include antibiotics, immunosuppressants, plant and animal toxins, and enzyme inhibitors. NRPS has a distinct modular structure in which each module is responsible for the recognition, activation, and in some cases, modification of a single amino acid residue of the final peptide product. The modules can be subdivided into domains that catalyze specific biochemical reactions. This family includes the myxovirescin (TA) antibiotic biosynthetic gene in Myxococcus xanthus; TA production plays a role in predation. It also includes the salinosporamide A polyketide synthase which is involved in the biosynthesis of salinosporamide A, a marine microbial metabolite whose chlorine atom is crucial for potent proteasome inhibition and anticancer activity.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|
gi 488471904  47 QVVSEDPLFILYTSGSTGKPKAIVHTHGGYqVGTYITLKQCFDIKEEDRW 96
Cdd:cd12116  122 PVSPDDLAYVIYTSGSTGRPKGVVVSHRNL-VNFLHSMRERLGLGPGDRL 170

acyl-CoA synthetase; Validated

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|..
gi 488471904  42 KCETVQVVSEDPLFILYTSGSTGKPKAIVHTHGgyQVGTYIT 83
Cdd:PRK07470 154 RVANAAVDHDDPCWFFFTSGTTGRPKAAVLTHG--QMAFVIT 193

Benzoate CoA ligase (BCL) and 4-Hydroxybenzoate-Coenzyme A Ligase (4-HBA-CoA ligase); Benzoate CoA ligase and 4-hydroxybenzoate-coenzyme A ligase catalyze the first activating step for benzoate and 4-hydroxybenzoate catabolic pathways, respectively. Although these two enzymes share very high sequence homology, they have their own substrate preference. The reaction proceeds via a two-step process; the first ATP-dependent step forms the substrate-AMP intermediate, while the second step forms the acyl-CoA ester, releasing the AMP. Aromatic compounds represent the second most abundant class of organic carbon compounds after carbohydrates. Some bacteria can use benzoic acid or benzenoid compounds as the sole source of carbon and energy through degradation. Benzoate CoA ligase and 4-hydroxybenzoate-Coenzyme A ligase are key enzymes of this process.

                         10        20
                 ....*....|....*....|...
gi 488471904  51 EDPLFILYTSGSTGKPKAIVHTH 73
Cdd:cd05959  163 DDPAFWLYSSGSTGRPKGVVHLH 185

Uncharacterized subfamily of fatty acid CoA ligase (FACL); Fatty acyl-CoA ligases catalyze the ATP-dependent activation of fatty acids in a two-step reaction. The carboxylate substrate first reacts with ATP to form an acyl-adenylate intermediate, which then reacts with CoA to produce an acyl-CoA ester. This is a required step before free fatty acids can participate in most catabolic and anabolic reactions.

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|....*.
gi 488471904  50 SEDPLFILYTSGSTGKPKAIVHTHGGYqVGTYITLKQCFDIKEEDR 95
Cdd:cd05910   84 ADEPAAILFTSGSTGTPKGVVYRHGTF-AAQIDALRQLYGIRPGEV 128

The adenylation domain (A domain) of a family of nonribosomal peptide synthetases (NRPSs) synthesizing toxins and antitumor agents; The adenylation (A) domain of NRPS recognizes a specific amino acid or hydroxy acid and activates it as an (amino)-acyl adenylate by hydrolysis of ATP. The activated acyl moiety then forms a thioester to the enzyme-bound cofactor phosphopantetheine of a peptidyl carrier protein domain. This family includes NRPSs that synthesize toxins and antitumor agents; for example, TubE for Tubulysine, CrpA for cryptophycin, TdiA for terrequinone A, KtzG for kutzneride, and Vlm1/Vlm2 for Valinomycin. Nonribosomal peptide synthetases are large multifunctional enzymes which synthesize many therapeutically useful peptides. NRPS has a distinct modular structure in which each module is responsible for the recognition, activation, and, in some cases, modification of a single amino acid residue of the final peptide product. The modules can be subdivided into domains that catalyze specific biochemical reactions.

                         10        20
                 ....*....|....*....|....*...
gi 488471904  46 VQVVSEDPLFILYTSGSTGKPKAIVHTH 73
Cdd:cd05906  162 PQSRPDDLALLMLTSGSTGFPKAVPLTH 189

Uncharacterized subfamily of fatty acid CoA ligase (FACL); Fatty acyl-CoA ligases catalyze the ATP-dependent activation of fatty acids in a two-step reaction. The carboxylate substrate first reacts with ATP to form an acyl-adenylate intermediate, which then reacts with CoA to produce an acyl-CoA ester. This is a required step before free fatty acids can participate in most catabolic and anabolic reactions.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*.
gi 488471904  44 ETVQVVSEDPLFILYTSGSTGKPKAIVHTHGGYQVGTYItLKQCFDIKEEDRWWCT 99
Cdd:cd05922  110 PAHEVSHEDLALLLYTSGSTGSPKLVRLSHQNLLANARS-IAEYLGITADDRALTV 164

putative crotonobetaine/carnitine-CoA ligase; Validated

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....
gi 488471904  43 CETVQVVSEDPLFILYTSGSTGKPKAIVHTHGGYQVGTYITLKQCfDIKEEDRW 96
Cdd:PRK08008 165 CYAPPLSTDDTAEILFTSGTTSRPKGVVITHYNLRFAGYYSAWQC-ALRDDDVY 217

The adenylation domain of nonribosomal peptide synthetases (NRPS), including Saframycin A gene cluster from Streptomyces lavendulae; The adenylation (A) domain of NRPS recognizes a specific amino acid or hydroxy acid and activates it as an (amino) acyl adenylate by hydrolysis of ATP. The activated acyl moiety then forms a thioester to the enzyme-bound cofactor phosphopantetheine of a peptidyl carrier protein domain. NRPSs are large multifunctional enzymes which synthesize many therapeutically useful peptides in bacteria and fungi via a template-directed, nucleic acid independent nonribosomal mechanism. These natural products include antibiotics, immunosuppressants, plant and animal toxins, and enzyme inhibitors. NRPS has a distinct modular structure in which each module is responsible for the recognition, activation, and in some cases, modification of a single amino acid residue of the final peptide product. The modules can be subdivided into domains that catalyze specific biochemical reactions. This family includes the saframycin A gene cluster from Streptomyces lavendulae which implicates the NRPS system for assembling the unusual tetrapeptidyl skeleton in an iterative manner. It also includes saframycin Mx1 produced by Myxococcus xanthus NRPS.

                         10        20        30
                 ....*....|....*....|....*....|...
gi 488471904  43 CETVQVVSEDPLFILYTSGSTGKPKAIVHTHGG 75
Cdd:cd12115   97 ARLVLTDPDDLAYVIYTSGSTGRPKGVAIEHRN 129

similar to adenylation domain of chondramide synthase cmdD; This family of the adenylation (A) domain of nonribosomal peptide synthases (NRPS) includes phosphinothricin tripeptide (PTT, phosphinothricylalanylalanine) synthetase, where PTT is a natural-product antibiotic and potent herbicide that is produced by Streptomyces hygroscopicus. This adenylation domain has been confirmed to directly activate beta-tyrosine, and fluorinated chondramides are produced through precursor-directed biosynthesis. Also included in this family is chondramide synthase D (also known as ATP-dependent phenylalanine adenylase or phenylalanine activase or tyrosine activase). Chondramides A-D are depsipeptide antitumor and antifungal antibiotics produced by C. crocatus, are a class of mixed peptide/polyketide depsipeptides comprised of three amino acids (alanine, N-methyltryptophan, plus the unusual amino acid beta-tyrosine or alpha-methoxy-beta-tyrosine) and a polyketide chain ([E]-7-hydroxy-2,4,6-trimethyloct-4-enoic acid).

                         10        20
                 ....*....|....*....|....*..
gi 488471904  49 VSEDPLFILYTSGSTGKPKAIVHTHGG 75
Cdd:cd17652   91 TPDNLAYVIYTSGSTGRPKGVVVTHRG 117

long-chain-fatty-acid--CoA ligase; Validated

                         10        20
                 ....*....|....*....|....*..
gi 488471904  48 VVSEDPLFILYTSGSTGKPKAIVHTHG 74
Cdd:PRK05605 216 PTPDDVALILYTSGTTGKPKGAQLTHR 242

Peptide Synthetase; The adenylation (A) domain of NRPS recognizes a specific amino acid or hydroxy acid and activates it as an (amino) acyl adenylate by hydrolysis of ATP. The activated acyl moiety then forms a thioester bond to the enzyme-bound cofactor phosphopantetheine of a peptidyl carrier protein domain. NRPSs are large multifunctional enzymes which synthesize many therapeutically useful peptides in bacteria and fungi via a template-directed, nucleic acid independent nonribosomal mechanism. These natural products include antibiotics, immunosuppressants, plant and animal toxins, and enzyme inhibitors. NRPS has a distinct modular structure in which each module is responsible for the recognition, activation, and in some cases, modification of a single amino acid residue of the final peptide product. The modules can be subdivided into domains that catalyze specific biochemical reactions.

                         10        20        30
                 ....*....|....*....|....*....|..
gi 488471904  44 ETVQVVSEDPLFILYTSGSTGKPKAIVHTHGG 75
Cdd:cd17646  131 PLVPPRPDNLAYVIYTSGSTGRPKGVMVTHAG 162

acyl-CoA synthetase; Validated

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....
gi 488471904  46 VQVVSEDPLFILYTSGSTGKPKAIVHTHGG----YqVGTYITLkqcfDIKEEDR 95
Cdd:PRK08316 166 VELADDDLAQILYTSGTESLPKGAMLTHRAliaeY-VSCIVAG----DMSADDI 214

o-succinylbenzoate--CoA ligase;

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 488471904  37 PIAKGKCETVQVVSEDPL----FILYTSGSTGKPKAIVHTHGGY---QVGTYITLkqcfDIKEEDRWWC 98
Cdd:PRK03640 123 ELMNGPKEEAEIQEEFDLdevaTIMYTSGTTGKPKGVIQTYGNHwwsAVGSALNL----GLTEDDCWLA 187

similar to adenylation domain of plipastatin synthase (PpsD); This family of the adenylation (A) domain of nonribosomal peptide synthases (NRPS) includes bacitracin synthetase 1 (BacA) in Bacillus licheniformis, tyrocidine synthetase in Brevibacillus brevis, plipastatin synthase (PpsD, an important antifungal protein) in Bacillus subtilis and mannopeptimycin peptide synthetase (MppB) in Streptomyces hygroscopicus. Plipastatin has strong fungitoxic activity and is involved in inhibition of phospholipase A2 and biofilm formation. Bacitracin, a mixture of related cyclic peptides, is used as a polypeptide antibiotic while function of tyrocidine is thought to be regulation of sporulation. MppB is involved in biosynthetic pathway of mannopeptimycin, a novel class of mannosylated lipoglycopeptides. The adenylation (A) domain of NRPS recognizes a specific amino acid or hydroxy acid and activates it as an (amino) acyl adenylate by hydrolysis of ATP. The activated acyl moiety then forms a thioester bond to the enzyme-bound cofactor phosphopantetheine of a peptidyl carrier protein domain. NRPSs are large multifunctional enzymes which synthesize many therapeutically useful peptides in bacteria and fungi via a template-directed, nucleic acid independent nonribosomal mechanism. These natural products include antibiotics, immunosuppressants, plant and animal toxins, and enzyme inhibitors. NRPS has a distinct modular structure in which each module is responsible for the recognition, activation, and in some cases, modification of a single amino acid residue of the final peptide product. The modules can be subdivided into domains that catalyze specific biochemical reactions.

                         10        20
                 ....*....|....*....|....*.
gi 488471904  51 EDPLFILYTSGSTGKPKAIVHTHGGY 76
Cdd:cd17650   93 EDLAYVIYTSGTTGKPKGVMVEHRNV 118

Uncharacterized subfamily of fatty acid CoA ligase (FACL); Fatty acyl-CoA ligases catalyze the ATP-dependent activation of fatty acids in a two-step reaction. The carboxylate substrate first reacts with ATP to form an acyl-adenylate intermediate, which then reacts with CoA to produce an acyl-CoA ester. This is a required step before free fatty acids can participate in most catabolic and anabolic reactions. Members of this family include DitJ from Pseudomonas and similar proteins.

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|....*....
gi 488471904  47 QVVSEDPLFILYTSGSTGKPKAIVHTHGGYQVGTYITLKQcFDIKEEDR 95
Cdd:cd05934   77 QLVVVDPASILYTSGTTGPPKGVVITHANLTFAGYYSARR-FGLGEDDV 124

The adenylation domain of nonribosomal peptide synthetases (NRPS), including Bacillus subtilis termination module Surfactin (SrfA-C); The adenylation (A) domain of NRPS recognizes a specific amino acid or hydroxy acid and activates it as an (amino) acyl adenylate by hydrolysis of ATP. The activated acyl moiety then forms a thioester to the enzyme-bound cofactor phosphopantetheine of a peptidyl carrier protein domain. NRPSs are large multifunctional enzymes which synthesize many therapeutically useful peptides in bacteria and fungi via a template-directed, nucleic acid independent nonribosomal mechanism. These natural products include antibiotics, immunosuppressants, plant and animal toxins, and enzyme inhibitors. NRPS has a distinct modular structure in which each module is responsible for the recognition, activation, and, in some cases, modification of a single amino acid residue of the final peptide product. The modules can be subdivided into domains that catalyze specific biochemical reactions. This family includes the adenylation domain of the Bacillus subtilis termination module (Surfactin domain, SrfA-C) which recognizes a specific amino acid building block, which is then activated and transferred to the terminal thiol of the 4'-phosphopantetheine (Ppan) arm of the downstream peptidyl carrier protein (PCP) domain.

                         10        20
                 ....*....|....*....|....
gi 488471904  50 SEDPLFILYTSGSTGKPKAIVHTH 73
Cdd:cd12117  135 PDDLAYVMYTSGSTGRPKGVAVTH 158

feruloyl-CoA synthase; Reviewed

                         10
                 ....*....|....*....
gi 488471904  56 ILYTSGSTGKPKAIVHTHG 74
Cdd:PRK08180 214 FLFTSGSTGLPKAVINTHR 232

Long-chain fatty acid CoA synthetases and Bubblegum-like very long-chain fatty acid CoA synthetases; This family includes long-chain fatty acid (C12-C20) CoA synthetases and Bubblegum-like very long-chain (>C20) fatty acid CoA synthetases. FACS catalyzes the formation of fatty acyl-CoA in a two-step reaction: the formation of a fatty acyl-AMP molecule as an intermediate, and the formation of a fatty acyl-CoA. Eukaryotes generally have multiple isoforms of LC-FACS genes with multiple splice variants. For example, nine genes are found in Arabidopsis and six genes are expressed in mammalian cells. Drosophila melanogaster mutant bubblegum (BGM) have elevated levels of very-long-chain fatty acids (VLCFA) caused by a defective gene later named bubblegum. The human homolog (hsBG) of bubblegum has been characterized as a very long chain fatty acid CoA synthetase that functions specifically in the brain; hsBG may play a central role in brain VLCFA metabolism and myelinogenesis. Free fatty acids must be "activated" to their CoA thioesters before participating in most catabolic and anabolic reactions.

                         10        20        30
                 ....*....|....*....|....*....|....
gi 488471904  45 TVQVVS--EDPLFILYTSGSTGKPKAIVHTHGGY 76
Cdd:cd05907   79 KALFVEdpDDLATIIYTSGTTGRPKGVMLSHRNI 112

acyl-CoA synthetase; Validated

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|....*..
gi 488471904  49 VSEDPLFILYTSGSTGKPKAIVHTHGGYqVGTYITLKQCFDIKEEDR 95
Cdd:PRK07638 141 VQNAPFYMGFTSGSTGKPKAFLRAQQSW-LHSFDCNVHDFHMKREDS 186

bifunctional acyl-ACP--phospholipid O-acyltransferase/long-chain-fatty-acid--ACP ligase;

                         10        20
                 ....*....|....*....|....
gi 488471904  50 SEDPLFILYTSGSTGKPKAIVHTH 73
Cdd:PRK08043 364 PEDAALILFTSGSEGHPKGVVHSH 387

Fatty acid transport proteins (FATP) play dual roles as fatty acid transporters and its activation enzymes; Fatty acid transport protein (FATP) transports long-chain or very-long-chain fatty acids across the plasma membrane. FATPs also have fatty acid CoA synthetase activity, thus playing dual roles as fatty acid transporters and its activation enzymes. At least five copies of FATPs are identified in mammalian cells. This family also includes prokaryotic FATPs. FATPs are the key players in the trafficking of exogenous fatty acids into the cell and in intracellular fatty acid homeostasis.

                         10        20        30
                 ....*....|....*....|....*....|
gi 488471904  52 DPLFILYTSGSTGKPKAIVHTHGGYQVGTY 81
Cdd:cd05940   82 DAALYIYTSGTTGLPKAAIISHRRAWRGGA 111

similar to adenylation domain of anabaenopeptin synthetase (ApnA); This family of the adenylation (A) domain of nonribosomal peptide synthases (NRPS) includes Planktothrix agardhii anabaenopeptin synthetase (ApnA A1), which is capable of activating two chemically distinct amino acids (Arg and Tyr). Structural studies show that the architecture of the active site forces Arg to adopt a Tyr-like conformation, thus explaining the bispecificity. The adenylation (A) domain of NRPS recognizes a specific amino acid or hydroxy acid and activates it as an (amino) acyl adenylate by hydrolysis of ATP. The activated acyl moiety then forms a thioester bond to the enzyme-bound cofactor phosphopantetheine of a peptidyl carrier protein domain. NRPSs are large multifunctional enzymes which synthesize many therapeutically useful peptides in bacteria and fungi via a template-directed, nucleic acid independent nonribosomal mechanism. These natural products include antibiotics, immunosuppressants, plant and animal toxins, and enzyme inhibitors. NRPS has a distinct modular structure in which each module is responsible for the recognition, activation, and in some cases, modification of a single amino acid residue of the final peptide product. The modules can be subdivided into domains that catalyze specific biochemical reactions.

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|....*
gi 488471904  51 EDPLFILYTSGSTGKPKAIVHTHGGYqVGTYITLKQCFDIKEEDR 95
Cdd:cd17644  106 ENLAYVIYTSGSTGKPKGVMIEHQSL-VNLSHGLIKEYGITSSDR 149

O-succinylbenzoic acid-CoA ligase; This family contains O-succinylbenzoyl-CoA (OSB-CoA) synthetase (also known as O-succinylbenzoic acid CoA ligase) that belongs to the ANL superfamily and catalyzes the ligation of CoA to o-succinylbenzoate (OSB). It includes MenE in the bacterial menaquinone biosynthesis pathway which is a promising target for the development of novel antibacterial agents. MenE catalyzes CoA ligation via an acyl-adenylate intermediate; tight-binding inhibitors of MenE based on stable acyl-sulfonyladenosine analogs of this intermediate provide a pathway toward the development of optimized MenE inhibitors.

                         10        20
                 ....*....|....*....|..
gi 488471904  52 DPLFILYTSGSTGKPKAIVHTH 73
Cdd:cd17630    1 RLATVILTSGSTGTPKAVVHTA 22

O-succinylbenzoic acid--CoA ligase; Provisional

                         10
                 ....*....|....*.
gi 488471904  59 TSGSTGKPKAIVHTHG 74
Cdd:PRK09029 143 TSGSTGLPKAAVHTAQ 158

long-chain-fatty-acid--CoA ligase; Validated

                         10
                 ....*....|....*...
gi 488471904  56 ILYTSGSTGKPKAIVHTH 73
Cdd:PRK06187 172 MLYTSGTTGHPKGVVLSH 189

nonribosomal peptide synthase GliP-like; This family includes the adenylation (A) domain of nonribosomal peptide synthases (NRPS) gliotoxin biosynthesis protein P (GliP), thioclapurine biosynthesis protein P (tcpP) and Sirodesmin biosynthesis protein P (SirP). In the filamentous fungus Aspergillus fumigatus, NRPS GliP is involved in the biosynthesis of gliotoxin, which is initiated by the condensation of serine and phenylalanine. Studies show that GliP is not required for invasive aspergillosis, suggesting that the principal targets of gliotoxin are neutrophils or other phagocytes. SirP is a phytotoxin produced by the fungus Leptosphaeria maculans, which causes blackleg disease of canola (Brassica napus). In the fungus Claviceps purpurea, NRPS tcpP catalyzes condensation of tyrosine and glycine, part of biosynthesis of an unusual class of epipolythiodioxopiperazines (ETPs) that lacks the reactive thiol group for toxicity. The adenylation (A) domain of NRPS recognizes a specific amino acid or hydroxy acid and activates it as an (amino) acyl adenylate by hydrolysis of ATP. The activated acyl moiety then forms a thioester bond to the enzyme-bound cofactor phosphopantetheine of a peptidyl carrier protein domain. NRPSs are large multifunctional enzymes which synthesize many therapeutically useful peptides in bacteria and fungi via a template-directed, nucleic acid independent nonribosomal mechanism. These natural products include antibiotics, immunosuppressants, plant and animal toxins, and enzyme inhibitors. NRPS has a distinct modular structure in which each module is responsible for the recognition, activation, and in some cases, modification of a single amino acid residue of the final peptide product. The modules can be subdivided into domains that catalyze specific biochemical reactions.

                         10        20
                 ....*....|....*....|....*
gi 488471904  51 EDPLFILYTSGSTGKPKAIVHTHGG 75
Cdd:cd17653  105 DDLAYIIFTSGSTGIPKGVMVPHRG 129

long-chain-fatty-acid-CoA ligase family protein

                         10        20
                 ....*....|....*....|....*
gi 488471904  50 SEDPLFILYTSGSTGKPKAIVHTHG 74
Cdd:PLN02387 249 PNDIAVIMYTSGSTGLPKGVMMTHG 273

Long-chain fatty acid CoA synthetase; This family includes long-chain fatty acid (C12-C20) CoA synthetases, including an Arabidopsis gene At4g14070 that plays a role in activation and elongation of exogenous fatty acids. FACS catalyzes the formation of fatty acyl-CoA in a two-step reaction: the formation of a fatty acyl-AMP molecule as an intermediate, and the formation of a fatty acyl-CoA. Eukaryotes generally have multiple isoforms of LC-FACS genes with multiple splice variants. For example, nine genes are found in Arabidopsis and six genes are expressed in mammalian cells. Free fatty acids must be "activated" to their CoA thioesters before participating in most catabolic and anabolic reactions.

                         10        20        30
                 ....*....|....*....|....*....|.
gi 488471904  50 SEDPLFILYTSGSTGKPKAIVHTHGG--YQV 78
Cdd:cd17640   87 SDDLATIIYTSGTTGNPKGVMLTHANllHQI 117

peptide synthase; Provisional

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|..
gi 488471904   55 FILYTSGSTGKPKAIVHTHGGYqVGTYITLKQCFDIKEEDRW 96
Cdd:PRK12467 1722 YVIYTSGSTGRPKGAGNRHGAL-VNRLCATQEAYQLSAADVV 1762

malonyl-CoA synthase; Validated

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|..
gi 488471904  44 ETVQVVSEDPLFILYTSGSTGKPKAIVHTHGGYqVGTYITLKQCFDIKEEDR 95
Cdd:PRK07514 149 ETVPRGADDLAAILYTSGTTGRSKGAMLSHGNL-LSNALTLVDYWRFTPDDV 199

acyl-CoA synthetase; Validated

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|...
gi 488471904  23 DLTCDHWYDELCKLPiakGKCETVQVVSEDPLFILY-TSGSTGKPKAIVHTHG 74
Cdd:PRK07867 126 NVDSPAWADELAAHR---DAEPPFRVADPDDLFMLIfTSGTSGDPKAVRCTHR 175