The membrane fatty acid desaturase (Membrane_FADS)-like CD includes membrane FADSs, alkane hydroxylases, beta carotene ketolases (CrtW-like), hydroxylases (CrtR-like), and other related proteins. They are present in all groups of organisms with the exception of archaea. Membrane FADSs are non-heme, iron-containing, oxygen-dependent enzymes involved in regioselective introduction of double bonds in fatty acyl aliphatic chains. They play an important role in the maintenance of the proper structure and functioning of biological membranes. Alkane hydroxylases are bacterial, integral-membrane di-iron enzymes that share a requirement for iron and oxygen for activity similar to that of membrane FADSs, and are involved in the initial oxidation of inactivated alkanes. Beta-carotene ketolase and beta-carotene hydroxylase are carotenoid biosynthetic enzymes for astaxanthin and zeaxanthin, respectively. This superfamily domain has extensive hydrophobic regions that would be capable of spanning the membrane bilayer at least twice. Comparison of these sequences also reveals three regions of conserved histidine cluster motifs that contain eight histidine residues: HXXX(X)H, HXX(X)HH, and HXXHH (an additional conserved histidine residue is seen between clusters 2 and 3). Spectroscopic and genetic evidence point to a nitrogen-rich coordination environment located in the cytoplasm with as many as eight histidines coordinating the two iron ions and a carboxylate residue bridging the two metals in the Pseudomonas oleovorans alkane hydroxylase (AlkB). In addition, the eight histidine residues are reported to be catalytically essential and proposed to be the ligands for the iron atoms contained within the rat stearoyl CoA delta-9 desaturase.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 157818323  86 SHLATHSALTESKRWSKiLMIFFVEVCTAFPAEFAKFNHvNMHHGYTNVLGlGDSSTWKMPLLnryvymllgpllvpllt 165
Cdd:cd03506   18 AHDAGHGQVFKNRWLNK-LLGLTVGNLLGASAGWWKNKH-NVHHAYTNILG-HDPDIDTLPLL----------------- 77

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 157818323 166 plvALEHLRKEELKTALRALGFiclglysQYWLFMNVSGFkspasALACMLLArSLLAHPYLHVNIF-QHIGLPMFSPDK 244
Cdd:cd03506   78 ---ARSEPAFGKDQKKRFLHRY-------QHFYFFPLLAL-----LLLAFLVV-QLAGGLWLAVVFQlNHFGMPVEDPPG 141

                        170       180       190       200       210
                 ....*....|....*....|....*....|....*....|....*....|....*....
gi 157818323 245 KPR--RIHMMTLGVLNLPRQPVLDWAFGHslISCHVEHHLFPWLSDHMCLKVKPVVSKF 301
Cdd:cd03506  142 ESKndWLERQVLTTRNITGSPFLDWLHGG--LNYQIEHHLFPTMPRHNYPKVAPLVREL 198

The Delta6 Fatty Acid Desaturase (Delta6-FADS)-like CD includes the integral-membrane enzymes: delta-4, delta-5, delta-6, delta-8, delta-8-sphingolipid, and delta-11 desaturases found in vertebrates, higher plants, fungi, and bacteria. These desaturases are required for the synthesis of highly unsaturated fatty acids (HUFAs), which are mainly esterified into phospholipids and contribute to maintaining membrane fluidity. While HUFAs may be required for cold tolerance in bacteria, plants and fish, the primary role of HUFAs in mammals is cell signaling. These enzymes are described as front-end desaturases because they introduce a double bond between the pre-exiting double bond and the carboxyl (front) end of the fatty acid. Various substrates are involved, with both acyl-coenzyme A (CoA) and acyl-lipid desaturases present in this CD. Acyl-lipid desaturases are localized in the membranes of cyanobacterial thylakoid, plant endoplasmic reticulum (ER), and plastid; and acyl-CoA desaturases are present in ER membrane. ER-bound plant acyl-lipid desaturases and acyl-CoA desaturases require cytochrome b5 as an electron donor. Most of the eukaryotic desaturase domains have an adjacent N-terminal cytochrome b5-like domain. This domain family has extensive hydrophobic regions that would be capable of spanning the membrane bilayer at least twice. Comparison of sequences also reveals the existence of three regions of conserved histidine cluster motifs that contain the residues: HXXXH, HXX(X)HH, and Q/HXXHH. These histidine residues are reported to be catalytically essential and proposed to be the ligands for the iron atoms contained within the homolog, stearoyl CoA desaturase.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 157818323  86 SHLATHSALTESKRWSKiLMIFFVEVCTAFPAEFAKFNHvNMHHGYTNVLGlGDSSTWKMPLLnryvymllgpllvpllt 165
Cdd:cd03506   18 AHDAGHGQVFKNRWLNK-LLGLTVGNLLGASAGWWKNKH-NVHHAYTNILG-HDPDIDTLPLL----------------- 77

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 157818323 166 plvALEHLRKEELKTALRALGFiclglysQYWLFMNVSGFkspasALACMLLArSLLAHPYLHVNIF-QHIGLPMFSPDK 244
Cdd:cd03506   78 ---ARSEPAFGKDQKKRFLHRY-------QHFYFFPLLAL-----LLLAFLVV-QLAGGLWLAVVFQlNHFGMPVEDPPG 141

                        170       180       190       200       210
                 ....*....|....*....|....*....|....*....|....*....|....*....
gi 157818323 245 KPR--RIHMMTLGVLNLPRQPVLDWAFGHslISCHVEHHLFPWLSDHMCLKVKPVVSKF 301
Cdd:cd03506  142 ESKndWLERQVLTTRNITGSPFLDWLHGG--LNYQIEHHLFPTMPRHNYPKVAPLVREL 198

Fatty acid desaturase; Fatty acid desaturases are enzymes that catalyze the insertion of a double bond at the delta position of fatty acids. There seem to be two distinct families of fatty acid desaturases which do not seem to be evolutionary related: Family 1 composed of Stearoyl-CoA desaturases (SCD) and Family 2 composed of Bacterial fatty acid desaturases, Plant stearoyl-acyl-carrier-protein desaturase and Cyanobacterial DesA. Members of this entry are ER integral membrane proteins that share the same mushroom-shaped fold consisting of four transmembrane helices (TM1-TM4) which anchor them to the membrane, capped by a cytosolic domain containing a unique 9-10 histidine- coordinating di metal (di-iron) catalytic centre. The structure of mouse stearoyl-CoA desaturase (SDC) revealed that TM2 and TM4 are longer than TM1 and TM3 and protrude into the cytosolic domain, providing three of the nine histidine residues that coordinate the two metal ions, while the other histidine residues are provided by the soluble domain in this enzyme.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 157818323   66 AFATGITILGVCHYTLTVKGSHLATHSALTESKRWSKILMIFFVEVC---TAFPAEFAKFNHvNMHHGYTNVLGlGDSST 142
Cdd:pfam00487   3 LALLLALLLGLFLLGITGSLAHEASHGALFKKRRLNRWLNDLLGRLAglpLGISYSAWRIAH-LVHHRYTNGPD-KDPDT 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 157818323  143 WKMPLLNRYVYMLLGPLLVPLLTPLVALEHLRKEELKTALRALGFICLGLYSQYWLFMNVSGFkSPASALACMLLARSLL 222
Cdd:pfam00487  81 APLASRFRGLLRYLLRWLLGLLVLAWLLALVLPLWLRRLARRKRPIKSRRRRWRLIAWLLLLA-AWLGLWLGFLGLGGLL 159

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 157818323  223 AHPYLHVNIFQHIGLPMF------SPDKKPRRIHMMTLGVLNLPrqPVLDWAFGHslISCHVEHHLFPWLSDHMCLKVKP 296
Cdd:pfam00487 160 LLLWLLPLLVFGFLLALIfnylehYGGDWGERPVETTRSIRSPN--WWLNLLTGN--LNYHIEHHLFPGVPWYRLPKLHR 235

                         250
                  ....*....|....*
gi 157818323  297 VVSKFLHDKRLPYNE 311
Cdd:pfam00487 236 RLREALPEHGLPYRS 250

The Delta6 Fatty Acid Desaturase (Delta6-FADS)-like CD includes the integral-membrane enzymes: delta-4, delta-5, delta-6, delta-8, delta-8-sphingolipid, and delta-11 desaturases found in vertebrates, higher plants, fungi, and bacteria. These desaturases are required for the synthesis of highly unsaturated fatty acids (HUFAs), which are mainly esterified into phospholipids and contribute to maintaining membrane fluidity. While HUFAs may be required for cold tolerance in bacteria, plants and fish, the primary role of HUFAs in mammals is cell signaling. These enzymes are described as front-end desaturases because they introduce a double bond between the pre-exiting double bond and the carboxyl (front) end of the fatty acid. Various substrates are involved, with both acyl-coenzyme A (CoA) and acyl-lipid desaturases present in this CD. Acyl-lipid desaturases are localized in the membranes of cyanobacterial thylakoid, plant endoplasmic reticulum (ER), and plastid; and acyl-CoA desaturases are present in ER membrane. ER-bound plant acyl-lipid desaturases and acyl-CoA desaturases require cytochrome b5 as an electron donor. Most of the eukaryotic desaturase domains have an adjacent N-terminal cytochrome b5-like domain. This domain family has extensive hydrophobic regions that would be capable of spanning the membrane bilayer at least twice. Comparison of sequences also reveals the existence of three regions of conserved histidine cluster motifs that contain the residues: HXXXH, HXX(X)HH, and Q/HXXHH. These histidine residues are reported to be catalytically essential and proposed to be the ligands for the iron atoms contained within the homolog, stearoyl CoA desaturase.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 157818323  86 SHLATHSALTESKRWSKiLMIFFVEVCTAFPAEFAKFNHvNMHHGYTNVLGlGDSSTWKMPLLnryvymllgpllvpllt 165
Cdd:cd03506   18 AHDAGHGQVFKNRWLNK-LLGLTVGNLLGASAGWWKNKH-NVHHAYTNILG-HDPDIDTLPLL----------------- 77

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 157818323 166 plvALEHLRKEELKTALRALGFiclglysQYWLFMNVSGFkspasALACMLLArSLLAHPYLHVNIF-QHIGLPMFSPDK 244
Cdd:cd03506   78 ---ARSEPAFGKDQKKRFLHRY-------QHFYFFPLLAL-----LLLAFLVV-QLAGGLWLAVVFQlNHFGMPVEDPPG 141

                        170       180       190       200       210
                 ....*....|....*....|....*....|....*....|....*....|....*....
gi 157818323 245 KPR--RIHMMTLGVLNLPRQPVLDWAFGHslISCHVEHHLFPWLSDHMCLKVKPVVSKF 301
Cdd:cd03506  142 ESKndWLERQVLTTRNITGSPFLDWLHGG--LNYQIEHHLFPTMPRHNYPKVAPLVREL 198

Fatty acid desaturase; Fatty acid desaturases are enzymes that catalyze the insertion of a double bond at the delta position of fatty acids. There seem to be two distinct families of fatty acid desaturases which do not seem to be evolutionary related: Family 1 composed of Stearoyl-CoA desaturases (SCD) and Family 2 composed of Bacterial fatty acid desaturases, Plant stearoyl-acyl-carrier-protein desaturase and Cyanobacterial DesA. Members of this entry are ER integral membrane proteins that share the same mushroom-shaped fold consisting of four transmembrane helices (TM1-TM4) which anchor them to the membrane, capped by a cytosolic domain containing a unique 9-10 histidine- coordinating di metal (di-iron) catalytic centre. The structure of mouse stearoyl-CoA desaturase (SDC) revealed that TM2 and TM4 are longer than TM1 and TM3 and protrude into the cytosolic domain, providing three of the nine histidine residues that coordinate the two metal ions, while the other histidine residues are provided by the soluble domain in this enzyme.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 157818323   66 AFATGITILGVCHYTLTVKGSHLATHSALTESKRWSKILMIFFVEVC---TAFPAEFAKFNHvNMHHGYTNVLGlGDSST 142
Cdd:pfam00487   3 LALLLALLLGLFLLGITGSLAHEASHGALFKKRRLNRWLNDLLGRLAglpLGISYSAWRIAH-LVHHRYTNGPD-KDPDT 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 157818323  143 WKMPLLNRYVYMLLGPLLVPLLTPLVALEHLRKEELKTALRALGFICLGLYSQYWLFMNVSGFkSPASALACMLLARSLL 222
Cdd:pfam00487  81 APLASRFRGLLRYLLRWLLGLLVLAWLLALVLPLWLRRLARRKRPIKSRRRRWRLIAWLLLLA-AWLGLWLGFLGLGGLL 159

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 157818323  223 AHPYLHVNIFQHIGLPMF------SPDKKPRRIHMMTLGVLNLPrqPVLDWAFGHslISCHVEHHLFPWLSDHMCLKVKP 296
Cdd:pfam00487 160 LLLWLLPLLVFGFLLALIfnylehYGGDWGERPVETTRSIRSPN--WWLNLLTGN--LNYHIEHHLFPGVPWYRLPKLHR 235

                         250
                  ....*....|....*
gi 157818323  297 VVSKFLHDKRLPYNE 311
Cdd:pfam00487 236 RLREALPEHGLPYRS 250