Isoprenoid Biosynthesis enzymes, Class 1; Superfamily of trans-isoprenyl diphosphate synthases (IPPS) and class I terpene cyclases which either synthesis geranyl/farnesyl diphosphates (GPP/FPP) or longer chained products from isoprene precursors, isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP), or use geranyl (C10)-, farnesyl (C15)-, or geranylgeranyl (C20)-diphosphate as substrate. These enzymes produce a myriad of precursors for such end products as steroids, cholesterol, sesquiterpenes, heme, carotenoids, retinoids, and diterpenes; and are widely distributed among archaea, bacteria, and eukaryota.The enzymes in this superfamily share the same 'isoprenoid synthase fold' and include several subgroups. The head-to-tail (HT) IPPS catalyze the successive 1'-4 condensation of the 5-carbon IPP to the growing isoprene chain to form linear, all-trans, C10-, C15-, C20- C25-, C30-, C35-, C40-, C45-, or C50-isoprenoid diphosphates. Cyclic monoterpenes, diterpenes, and sesquiterpenes, are formed from their respective linear isoprenoid diphosphates by class I terpene cyclases. The head-to-head (HH) IPPS catalyze the successive 1'-1 condensation of 2 farnesyl or 2 geranylgeranyl isoprenoid diphosphates. Cyclization of these 30- and 40-carbon linear forms are catalyzed by class II cyclases. Both the isoprenoid chain elongation reactions and the class I terpene cyclization reactions proceed via electrophilic alkylations in which a new carbon-carbon single bond is generated through interaction between a highly reactive electron-deficient allylic carbocation and an electron-rich carbon-carbon double bond. The catalytic site consists of a large central cavity formed by mostly antiparallel alpha helices with two aspartate-rich regions located on opposite walls. These residues mediate binding of prenyl phosphates via bridging Mg2+ ions, inducing proposed conformational changes that close the active site to solvent, stabilizing reactive carbocation intermediates. Generally, the enzymes in this family exhibit an all-trans reaction pathway, an exception, is the cis-trans terpene cyclase, trichodiene synthase. Mechanistically and structurally distinct, class II terpene cyclases and cis-IPPS are not included in this CD.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1230839525   1 MKIVDEREKNLDDKAYRNIKELENYAENTQSSLLYLTLEILGI--KDLHADHAASHIGKAQGIVTCLRATPYHGSRRKVF 78
Cdd:pfam00494  92 LELIDGMEMDLEFTRYETLAELEEYCYYVAGVVGLLLLRLLGArsDEAALLEAASHLGLALQLTNILRDVGEDARRGRVY 171

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1230839525  79 LPMDICMLHGVSQEDFLRRNQDKNVRDVIYDIASQAHLHLKHARSFHKTVPVKAFPAFLQTVSL-EDFLKKIQRVDFDIF 157
Cdd:pfam00494 172 LPAEVLKRFGVSEEDLLRGRASPALRALLRELAERARAHLREARPLLALLPRRARPAVLLAAVLyRAILRRLEAAGYDVL 251

                  ..
gi 1230839525 158 HP 159
Cdd:pfam00494 252 RR 253

Squalene/phytoene synthase;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1230839525   1 MKIVDEREKNLDDKAYRNIKELENYAENTQSSLLYLTLEILGI--KDLHADHAASHIGKAQGIVTCLRATPYHGSRRKVF 78
Cdd:pfam00494  92 LELIDGMEMDLEFTRYETLAELEEYCYYVAGVVGLLLLRLLGArsDEAALLEAASHLGLALQLTNILRDVGEDARRGRVY 171

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1230839525  79 LPMDICMLHGVSQEDFLRRNQDKNVRDVIYDIASQAHLHLKHARSFHKTVPVKAFPAFLQTVSL-EDFLKKIQRVDFDIF 157
Cdd:pfam00494 172 LPAEVLKRFGVSEEDLLRGRASPALRALLRELAERARAHLREARPLLALLPRRARPAVLLAAVLyRAILRRLEAAGYDVL 251

                  ..
gi 1230839525 158 HP 159
Cdd:pfam00494 252 RR 253

Trans-Isoprenyl Diphosphate Synthases, head-to-head; These trans-Isoprenyl Diphosphate Synthases (Trans_IPPS) catalyze a head-to-head (HH) (1'-1) condensation reaction. This CD includes squalene and phytoene synthases which catalyze the 1'-1 condensation of two 15-carbon (farnesyl) and 20-carbon (geranylgeranyl) isoprenyl diphosphates, respectively. The catalytic site consists of a large central cavity formed by mostly antiparallel alpha helices with two aspartate-rich regions (DXXXD) located on opposite walls. These residues mediate binding of prenyl phosphates. A two-step reaction has been proposed for squalene synthase (farnesyl-diphosphate farnesyltransferase) in which, two molecules of FPP react to form a stable cyclopropylcarbinyl diphosphate intermediate, and then the intermediate undergoes heterolysis, isomerization, and reduction with NADPH to form squalene, a precursor of cholestrol. The carotenoid biosynthesis enzyme, phytoene synthase (CrtB), catalyzes the condensation reaction of two molecules of geranylgeranyl diphosphate to produce phytoene, a precursor of beta-carotene. These enzymes produce the triterpene and tetraterpene precursors for many diverse sterol and carotenoid end products and are widely distributed among eukareya, bacteria, and archaea.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1230839525   8 EKNLDDKAYRNIKELENYAENTQSSLLYLTLEILGIKDLH-ADHAASHIGKAQGIVTCLR--ATPYHGSRrkVFLPMDIC 84
Cdd:cd00683   103 AMDLDKRRYETLDELDEYCYYVAGVVGLMLLRVFGASSDEaALERARALGLALQLTNILRdvGEDARRGR--IYLPREEL 180

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 1230839525  85 MLHGVSQEDFLRRNQDKNVRDVIYDIASQAHLHLKHARSFHKTVPVKA-FPAFLQTVSLEDFLKKIQRVDFDIFH 158
Cdd:cd00683   181 ARFGVTLEDLLAPENSPAFRALLRRLIARARAHYREALAGLAALPRRSrFCVRAAAMLYRTILDEIEARGYDVLS 255

Squalene/phytoene synthase;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1230839525   1 MKIVDEREKNLDDKAYRNIKELENYAENTQSSLLYLTLEILGI--KDLHADHAASHIGKAQGIVTCLRATPYHGSRRKVF 78
Cdd:pfam00494  92 LELIDGMEMDLEFTRYETLAELEEYCYYVAGVVGLLLLRLLGArsDEAALLEAASHLGLALQLTNILRDVGEDARRGRVY 171

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1230839525  79 LPMDICMLHGVSQEDFLRRNQDKNVRDVIYDIASQAHLHLKHARSFHKTVPVKAFPAFLQTVSL-EDFLKKIQRVDFDIF 157
Cdd:pfam00494 172 LPAEVLKRFGVSEEDLLRGRASPALRALLRELAERARAHLREARPLLALLPRRARPAVLLAAVLyRAILRRLEAAGYDVL 251

                  ..
gi 1230839525 158 HP 159
Cdd:pfam00494 252 RR 253

Trans-Isoprenyl Diphosphate Synthases, head-to-head; These trans-Isoprenyl Diphosphate Synthases (Trans_IPPS) catalyze a head-to-head (HH) (1'-1) condensation reaction. This CD includes squalene and phytoene synthases which catalyze the 1'-1 condensation of two 15-carbon (farnesyl) and 20-carbon (geranylgeranyl) isoprenyl diphosphates, respectively. The catalytic site consists of a large central cavity formed by mostly antiparallel alpha helices with two aspartate-rich regions (DXXXD) located on opposite walls. These residues mediate binding of prenyl phosphates. A two-step reaction has been proposed for squalene synthase (farnesyl-diphosphate farnesyltransferase) in which, two molecules of FPP react to form a stable cyclopropylcarbinyl diphosphate intermediate, and then the intermediate undergoes heterolysis, isomerization, and reduction with NADPH to form squalene, a precursor of cholestrol. The carotenoid biosynthesis enzyme, phytoene synthase (CrtB), catalyzes the condensation reaction of two molecules of geranylgeranyl diphosphate to produce phytoene, a precursor of beta-carotene. These enzymes produce the triterpene and tetraterpene precursors for many diverse sterol and carotenoid end products and are widely distributed among eukareya, bacteria, and archaea.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1230839525   8 EKNLDDKAYRNIKELENYAENTQSSLLYLTLEILGIKDLH-ADHAASHIGKAQGIVTCLR--ATPYHGSRrkVFLPMDIC 84
Cdd:cd00683   103 AMDLDKRRYETLDELDEYCYYVAGVVGLMLLRVFGASSDEaALERARALGLALQLTNILRdvGEDARRGR--IYLPREEL 180

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 1230839525  85 MLHGVSQEDFLRRNQDKNVRDVIYDIASQAHLHLKHARSFHKTVPVKA-FPAFLQTVSLEDFLKKIQRVDFDIFH 158
Cdd:cd00683   181 ARFGVTLEDLLAPENSPAFRALLRRLIARARAHYREALAGLAALPRRSrFCVRAAAMLYRTILDEIEARGYDVLS 255