FATTY ACIDS: METHYLENE-INTERRUPTED DOUBLE BONDS

Transcription

1 Ftty cids: methylene-interrupted duble bnds - structures, ccurrence nd bichemistry FATTY ACIDS: METHYLENE-INTERRUPTED DOUBLE BONDS STRUCTURES, OCCURRENCE AND BIOCHEMISTRY Structure nd Nmenclture The lipids f ll higher rgnisms cntin pprecible quntities f plyunsturted ftty cids ( PUFA ) with methylene-interrupted duble bnds, i.e. with tw r mre duble bnds f the cis-cnfigurtin seprted by single methylene grup. The term hm-llylic is ccsinlly CH CH CH CH CH2 used t describe this mleculr feture. In higher plnts, the number f duble bnds in ftty cids nly rrely exceeds three, but in lge nd nimls there cn be up t six. Tw principl fmilies f plyunsturted ftty cids ccur in nture tht re derived bisyntheticlly frm linleic (9-cis,12-cis-ctdecdienic) nd α-linlenic (9-cis,12-cis,15-cis-ctdectrienic) cids. linleic cid COOH α-linlenic cid COOH In the shrthnd nmenclture, these re designted 9c,12c-18:2 nd 9c,12c,15c-18:3 respectively. The number befre the cln specifies the number f crbn tms, nd tht fter the cln, the number f duble bnds. The psitin f the terminl duble bnd cn be dented in the frm (n-x), where n is the chin-length f the ftty cid nd x is the number f crbn tms frm the lst duble bnd, ssuming tht ll the ther duble bnds re methylene-interrupted. Thus linlete nd α-linlente re 18:2(n-6) nd 18:3(n-3), respectively (18:2ω6 nd 18:3ω3 in the lder literture). Bth f the prent ftty cids cn be synthesised in plnts, but nt in niml tissues, nd they re therefre essentil dietry cmpnents (see belw). Plyunsturted ftty cids cn be fund in mst lipid clsses, but they re especilly imprtnt s cnstituents f the phsphlipids, where they pper t cnfer distinctive prperties t the membrnes, in prticulr by decresing their rigidity. The exceptin is the sphinglipids, where they re rrely detected in ther thn trce munts. The (n-6) Fmily f Plyunsturted Ftty Acids Linleic cid is ubiquitus cmpnent f plnt lipids, nd f ll the seed ils f cmmercil imprtnce. Fr exmple, crn, sunflwer nd syben ils usully cntin ver 50% f linlete, nd sfflwer il cntins up t 75%. Althugh ll the linlete in niml tissues must be cquired frm the diet, it is usully the mst bundnt dienic ftty cid in mmmls (nd in mst lipid W.W. Christie lipidlibrry.cs.rg 1

2 Ftty cids: methylene-interrupted duble bnds - structures, ccurrence nd bichemistry clsses) typiclly t levels f 15 t 25%, lthugh it cn munt t s much s 75% f the ttl ftty cids f hert crdilipin. It is ls significnt cmpnent f fish ils, lthugh ftty cids f the (n-3) fmily tend t predminte in this instnce. Anlgues f linleic cid with trns-duble bnds re ccsinlly fund in seed ils. Fr exmple 9c,12t-18:2 is reprted frm Dimrphthec nd Crepis species, nd 9t,12t-18:2 is fund in Chilpsis lineris. The remining members f the (n-6) fmily f ftty cids re synthesised frm linlete in niml nd plnt tissues by sequence f elngtin nd desturtin rectins s described belw. The intermedites cn functin s essentil ftty cids ls. Shrter-chin cmpnents my be prduced by lph r bet-xidtin. γ-linlenic cid ( GLA r 6-cis,9-cis,12-cis-ctdectrienic cid r 18:3(n-6)) is usully minr cmpnent f niml tissues in quntittive terms (< 1%), s it is rpidly cnverted t higher metblites. It is fund in few seed ils, nd thse f evening primrse, brge nd blckcurrnt hve sme cmmercil imprtnce. Evening primrse il cntins but 10% GLA, nd is widely used bth s nutrceuticl nd medicl/veterinry prduct. 11-cis,14-cis-Eicsdienic cid (20:2(n-6)) is cmmn minr cmpnent f niml tissues. 8-cis,11-cis,14-cis-Eicstrienic cid (dihm-γ-linlenic cid r 20:3(n-6)) is the immedite precursr f rchidnic cid, nd f fmily f eicsnids (PG 1 prstglndins). Hwever, it des nt ccumulte t significnt extent in niml tissue lipids, nd is typiclly but 1-2% f the phsphlipid ftty cids. Archidnic cid (5-cis,8-cis,11-cis,14-cis-eicstetrenic cid r 20:4(n-6)) is the mst imprtnt metblite f linleic cid in niml tissues, bth in quntittive nd bilgicl terms. It is ften the mst bundnt plyunsturted cmpnent f the phsphlipids, nd cn cmprise s much s 40% f the ftty cids f phsphtidylinsitl. As such, it hs n bvius rle in regulting the physicl prperties f membrnes, but the free cid ls is invlved in the mechnism by which pptsis is COOH regulted. rchidnic cid Met is the min dietry surce in humns. While rchidnte is present in ll fish ils, plyunsturted ftty cids f the (n-3) fmilies tend t be present in much lrger munts. Archidnic cid is frequently fund s cnstituent f msses, liverwrts nd ferns, but there ppers t be nly ne definitive reprt f its ccurrence in higher plnt (Agthis rbust). The fungus Mrtierell lpin is cmmercil surce r rchidnte vi fermenttin prcess. Severl fmilies f eicsnids re derived frm rchidnte, including prstglndins (PG 2 series), thrmbxnes, leuktrienes, nd lipxins, with phsphtidylinsitl being the primry surce. These hve n enrmus rnge f essentil bilgicl functins tht re discussed in elsewhere in these web pges. In dditin, 2-rchidnylglycerl nd nndmide (Nrchidnylethnlmine) hve imprtnt bilgicl prperties s endcnnbinids, lthugh they re minr lipids in tissues in quntittive terms. 4,7,10,13,16-Dcspentenic cid (22:5(n-6)) is usully reltively minr cmpnent f niml lipids, but it is the min C 22 plyunsturted ftty cid in the phsphlipids f testes. It cn munt t 70% f the lysbisphsphtidic cid in this tissue, fr exmple. In this instnce, C 22 ftty cids f the (n-3) fmily re present t reltively lw levels, in cntrst t mst ther reprductive tissues. W.W. Christie lipidlibrry.cs.rg 2

3 Ftty cids: methylene-interrupted duble bnds - structures, ccurrence nd bichemistry Other ftty cids f the (n-6) fmily tht re fund in niml tissues include 22:3(n-6) nd 22:4(n-6). The lst f these, 7,10,13,16-dcstetrenic r drenic cid, is significnt cmpnent f the phsphlipids f the drenl glnds nd f testes. Tetr- nd pentenic ftty cids f the (n-6) fmily frm C 24 t C 30 hve been fund in testes, nd even lnger hmlgues ccur in retin. Thse in testes re knwn t be essentil fr mle fertility nd sperm mturtin. Very-lng-chin ftty cids f this type were first reprted frm humn brin in ptients with the rre inherited disrder, Zellweger's syndrme, but it is nw estblished tht such ftty cids with up t 38 crbn tms nd with frm 3 t 6 methylene-interrupted duble bnds re present t lw levels the brin f nrml yung humns, with 34:4(n-6) nd 34:5(n-6) tending t predminte. The functin f these is nt knwn. The mst highly unsturted ftty cid f the (n-6) fmily t hve been chrcterized re 28:7(n-6) (4,7,10,13,16,19,22-ctcsheptente), which hs been fund in the lipids f mrine dinflgelltes nd herring muscle, nd 4,7,10,13,16,19,22,25,28-tetrtricntnnenic cid (34:9(n-6)) frm the freshwter crustcen species Bthynell ntns. The (n-3) Fmily f Plyunsturted Ftty Acids α-linlenic cid (9-cis,12-cis,15-cis-ctdectrienic cid r 18:3(n-3)) is mjr cmpnent f the leves nd especilly f the phtsynthetic pprtus f lge nd higher plnts, where mst f it is synthesised. It cn munt t 65% f the ttl ftty cids f linseed il, where its reltive susceptibility t xidtin hs prcticl cmmercil vlue in pints nd relted prducts. In cntrst, syben nd rpeseed ils hve up t 7% f linlente, nd this reduces the vlue f these ils fr cking purpses. α-linlenic cid is the bisynthetic precursr f jsmntes in plnts, which pper t hve functins tht prllel thse f the eicsnids in nimls. In niml tissue lipids, α-linlenic cid tends t be minr cmpnent (<1%), the exceptin being grss-eting nn-ruminnts such s the hrse r gse, where it cn munt t s much s 10% f the dipse tissue lipids. As with linlete, the remining members f the (n-3) fmily f ftty cids re synthesised frm α-linlente in niml nd plnt tissues by sequence f elngtin nd desturtin rectins s described belw, while shrter-chin cmpnents my ls be prduced by lph r betxidtin. They re essentil ftty cids. 11,14,17-Eicstrienic cid (20:3(n-3)) cn usully be detected in the phsphlipids f niml tissues but rrely t bve 1% f the ttl. Smewht higher cncentrtins my be fund in fish ils. Steridnic cid (6,9,12,15-ctdectetrenic r 18:4(n-3)) is ccsinlly fund in seed ils s minr cmpnent, nd it ccurs in lge nd fish ils. 3,6,9,12,15-Octdecpentenic cid r 18:5(n-3) is significnt cmpnent f the lipids f dinflgelltes, nd it cn enter the mrine fd chin frm this surce. 8,11,14,17-Eicstetrenic cid (20:4(n-3)) is fund in mst fish ils nd s minr cmpnent f niml phsphlipids. It is frequently encuntered in lge nd msses, but rrely in higher plnts. 5,8,11,14,17-Eicspentenic cid ( EPA r 20:5(n-3)) is ne f the mst imprtnt ftty cids f the (n-3) fmily. It ccurs widely in lge nd in fish ils, which re mjr cmmercil surces, but there re few definitive reprts f its ccurrence in higher plnts. It is n imprtnt cnstituent f the phsphlipids in niml tissues, COOH eicspentenic cid (20:5(n-3)) W.W. Christie lipidlibrry.cs.rg 3

4 Ftty cids: methylene-interrupted duble bnds - structures, ccurrence nd bichemistry especilly in brin, nd it is the precursr f the PG 3 series f prstglndins nd reslvins, which hve nti-inflmmtry effects (see the pprprite web pge). There is currently gret interest in the rle f this cid in lleviting the symptms f neurlgicl disrders such s schizphreni. 7,10,13,16,19-Dcspentenic cid (22:5(n-3)) is n imprtnt cnstituent f fish ils, nd it is usully present in niml phsphlipids t level f 2 t 5%. A lck f vilbility f the pure ftty cid hs ment tht it hs been reltively little studied, but it is knwn tht it cn be retr-cnverted t EPA lthugh desturtin t DHA des nt pper t ccur. It rects with lipxygenses t frm distinctive metblites. 4,7,10,13,16,19-Dcshexenic cid ( DHA r 22:6(n-3)) is usully the end pint f α-linlenic cid metblism in niml tissues. It is mjr cmpnent f fish ils, especilly frm tun eyeblls, nd f niml phsphlipids, thse f brin synpses nd retin cntining prticulrly high prprtins. Indeed, there is sme evidence tht incresed levels f this ftty cid re crrelted with imprved cgnitive nd behviurl functin in the develpment f the humn infnt, lthugh this is cntrversil. Dietry supplements my ls benefit the elderly. DHA is nt present in higher plnts, but it is fund in high cncentrtins in mny species f lge, especilly thse f mrine rigin. Indeed, it hs been rgued COOH tht micr-lge in qutic systems re the mjr surce f DHA nd EPA in fish, nd vi the fd chin cntribute substntilly t the levels f these dcshexenic cid ftty cids in terrestril systems including humns. DHA is nt substrte fr the prstglndin synthse/cyclxygense enzymes, nd indeed it inhibits them. Hwever, vi the ctin f lipxygenses, it is the precursr f the dcsnids, termed reslvins r prtectins, which re nlgus t the eicsnids but hve ptent ntiinflmmtry nd immun-regultry ctins. The cncentrtin f DHA in tissues hs been crrelted with number f humn disese sttes, nd it is essentil t mny neurlgicl functins. Prticulr ttentin hs been given t its rle in the retin where it is mjr structurl cmpnent f the phtreceptr uter segment membrnes. Fr exmple, it binds strngly t specific sites n rhdpsin, the primry light receptr in the eye, mdifying its stbility nd ctivity. It ffects signlling mechnisms invlved in phttrnsductin, enhncing ctivtin f membrne-bund retinl prteins, nd it my be invlved in rhdpsin regenertin. In sme cses, sight defects hve been melirted with DHA supplementtin. It is intimtely invlved with phsphtidylserine metblism in neurnl tissue. DHA is believed t hve specific effects n gene trnscriptin tht regulte number f prteins invlved in ftty cid synthesis nd desturtin, fr exmple. It hs been demnstrted t hve beneficil effects upn inflmmtry disrders f the intestine nd in reducing the risk f cln cncer, which my be medited thrugh sscitins with specific signlling prteins in membrnes. As phsphlipid cnstituent, it hs prfund effects n the prperties f membrnes, mdulting their structure nd functin. In such n envirnment, DHA is believed t be mre cmpct thn mre sturted chins with n verge length f 8.2Å t 41 C cmpred t 14.2Å fr leic chins. This is the result f dptin f cnfrmtin with prnunced twists f the chin, which reduce the distnce between the ends. The methyl grup with its extr bulk is lcted in the interir regin. In mixed-chin phsphlipids, further cnsequence is mrked increse in the cnfrmtinl disrder f the sturted chin. There ppers t be n incmptibility between the rigid structure f chlesterl nd the highly flexible chins f DHA, prmting the lterl segregtin f membrnes int PUFA-rich/chlesterl-pr nd PUFA-pr/chlesterl-rich regins. The ltter my ultimtely becme the membrne micrdmins knwn s rfts. W.W. Christie lipidlibrry.cs.rg 4

5 Ftty cids: methylene-interrupted duble bnds - structures, ccurrence nd bichemistry PUFA-rich/chlesterl-pr membrne micrdmins re techniclly less esy t study thn rfts, but they my ls cntin distinctive prteins nd hve imprtnt bilgicl functins. It hs been prpsed tht chnges in the cnfrmtin f signlling prteins when they mve between these very different dmins my hve the ptentil t mdulte cell functin in mnner tht my explin sme f the helth benefits f dietry cnsumptin f DHA. As with the (n-6) fmily, very-lng-chin ftty cids (C 24 t C 38 ) f the (n-3) fmilies ccur in the retin, brin nd sperm. They re derived bisyntheticlly by elngtin f the C 20 nd C 22 plyunsturted precursrs. Other ftty cids f the (n-3) fmily tht re fund in nture include 22:3(n-3) frm niml tissues nd 16:3(n-3), which is cmmn cnstituent f lef lipids (see ur web pges n mn-nd diglctsyldicylglycerls). 16:4(n-3), 16:4(n-3), 21:5(n-3), 24:5(n-3) nd 24:6(n-3) re ccsinlly present in mrine rgnisms, including fish. Heptenic ftty cids f the (n-3) fmily (38:7(n 3) nd 40:7(n 3)) hve been reprted frm brins f ptients with defined genetic defect, but the mst highly unsturted ftty cid f the n-3 fmily yet fund is 4,7,10,13,16,19,22,25-ctcsctente (28:8(n-3)) frm mrine dinflgelltes. The (n-9) Fmily f Plyunsturted Ftty Acids Olete cn be chin elngted nd desturted in niml tissues with 5,8,11-eicstrienic cid (20:3(n-9) r Med s cid ) s the mst imprtnt prduct. This nly ccumultes in tissues when the nimls re suffering frm essentil ftty cid deficiency (see belw). Other ftty cids f this fmily tht my ls be fund t lw levels include 18:2(n-9), 20:2(n-9) nd 22:3(n-9). Other Fmilies f Plyunsturted Ftty Acids 9,12-Hexdecdienic cid (16:2(n-4)) is fund in mrine micrrgnisms nd is presumbly the bisynthetic precursr f ther ftty cids with n (n-4) terminl structure, i.e. 18:2(n-4), 20:2(n-4), 16:3(n-4) nd 18:3(n-4). Ftty cids f n (n-1) fmily, ls fund in mrine rgnisms, re believed t be derived bisyntheticlly by further desturtin ( 15) f 6,9,12-hexdectrienic cid (16:3n-4)). The min nturlly ccurring ftty cids f this type re 16:4(n-1) nd 18:4(n-1), but 18:5(n-1) hs ls been detected. Trce munts f plyunsturted ftty cids f n (n-7) fmily re ccsinlly encuntered in mrine rgnisms nd re presumbly metblites f 9-16:1. Bisynthesis f Linleic nd Linlenic Acids Linleic nd α-linlenic cids re synthesised in plnt tissues frm leic cid by the intrductin f duble bnds between the existing duble bnd nd the terminl methyl grup by the sequentil ctin f 12 nd 15 desturses. 9-18:1 n-9 12 desturse 9,12-18:2 n-6 15 desturse 9,12,15-18:3 n-3 The min substrte fr the 12 desturse is 1-cyl,2-leyl-phsphtidylchline in the endplsmic reticulum f the cell (lthugh ther lipids my ls be substrtes in chlrplsts). The newly frmed linlete is then trnsferred by vriety f mechnisms t ther lipids. Phsphtidylchline cn ls be the substrte fr further desturtin, but in lef tissue in number f plnt species it ppers tht mst α-linlente is frmed by desturtin f linleic cid W.W. Christie lipidlibrry.cs.rg 5

6 Ftty cids: methylene-interrupted duble bnds - structures, ccurrence nd bichemistry linked t mnglctsyldicylglycerls. Thse plnts tht prduce significnt munts f 16:3(n-3) dd further cmplictins t the prblem, nd it is evident tht much remins t be lerned f the verll prcess. In fct, tw distinct desturses hve been chrcterized tht cn insert the 12 duble bnd, i.e. plstidil enzyme (FAD6), which uses the terminl methyl grup s reference pint nd is n ω6 desturse s it intrduces the duble bnd six crbns frm the terminl crbn, nd secndly n extr-plstidil lete 12 desturse (FAD2) tht is selective fr C12,13 xidtin independently f chin length. The ltter is relted clsely t n enzyme in the seeds f cstr il (Ricinus cmmunis) tht cnverts lete t (R)-12-hydrxysterte. Indeed, whether the prduct is hydrxyl grup r duble bnd my depend n the nture f nly fur min cid residues. Less is knw f the desturse (FAD3) tht cnverts linlete t α-linlente, but it is rgued tht it shuld be cnsidered s n ω3 rther thn s 15 enzyme. It ls hs much in cmmn with hydrxylse enzymes. Infrequently in plnts, duble bnd is inserted between n existing duble bnd nd the crbxyl grup s in the bisynthesis f γ-linlenic cid in evening primrse nd brge seed ils. 9-18:1 n-9 12 desturse 9,12-18:2 n-6 6 desturse 6,9,12-18:3 n-6 In this instnce, the duble in psitin 6 is inserted fter thse in psitins 9 nd 12. These prcesses re discussed in much mre detil in web pge in the plnt bichemistry sectin f this site. linleic 9,12-18:2 (frm the diet) Bisynthesis f the (n-6) Fmily f Plyunsturted Ftty Acids γ-linlenic 6-desturse 6,9,12-18:3 In niml tissues, dditinl duble bnds cn nly be inserted between n existing duble bnd nd the crbxyl grup. The linleic cid, which is the primry precursr mlecule fr the (n-6) fmily f ftty cids, must cme frm the diet. Bisynthesis f plyunsturted ftty cids requires sequence f chin elngtin nd desturtin steps, s illustrted, nd the vrius enzymes require the cylcenzyme A esters s substrtes nt intct lipids (unlike plnts). The liver is the min rgn invlved in the prcess. The first step is believed t be rte limiting nd invlves desturtin with the intrductin f duble bnd in psitin 6 t frm γ-linlenic cid. Chin elngtin dihm-γ-linlenic 8,11,14-20:3 prstglndin PG 1 5-desturse rchidnic 5,8,11,14-20:4 prstglndin PG 2 nd ther eicsnids elngtin 7,10,13,16-22:4 elngtin 9,12,15,18-24:4 6-desturse 6,9,12,15,18-24:5 retr-cnversin 4,7,10,13,16-22:5 W.W. Christie lipidlibrry.cs.rg 6

7 Ftty cids: methylene-interrupted duble bnds - structures, ccurrence nd bichemistry elngtin by tw-crbn unit gives 20:3(n-6), which is cnverted t rchidnic cid by 5 desturse. This is the min end prduct f the prcess. Hwever, further chin-elngtin steps yield first 22:4(n-6) nd then 24:4(n-6), which cn be further desturted by 6 desturse t 24:5(n-6). At lest three elngses, designted ELOVL2, 4, nd 5, hve been chrcterized f which ELOVL4 is especilly imprtnt in the retin nd ELOVL5 in liver. All the enzymes t this stge re lcted in the endplsmic reticulum f the cell, but the lst ftty cid (24:5(n-6) must be trnsferred t the perxismes fr retr-cnversin (β-xidtin) t 22:5(n-6). The mrine prsitic prtzn Perkinus mrinus (nd t lest three ther unrelted unicellulr rgnisms) synthesises rchidnic cid by n lterntive pthwy in which elngtin f linleic t 11,14-eicsdienic cid is fllwed by sequentil desturtin by 8 nd 5 desturses. These enzymes re nw knwn t be present in mmmls, lthugh the extent f their prticiptin in synthesis f plyunsturted ftty cids in viv is uncertin. Bisynthesis f the (n-3) Fmily f Plyunsturted Ftty Acids Agin, the α-linlenic cid, which is the primry precursr mlecule fr the (n-3) fmily f ftty cids in niml tissues, must cme frm the diet. The min pthwy t the frmtin f dcshexenic cid (22:6(n-3)) requires sequence f chin elngtin nd desturtin steps ( 5 nd 6 desturses), s illustrted belw, with cyl-cenzyme A esters s substrtes. α-linlenic 9,12,15-18:3 (frm the diet) 6-desturse steridnic 6,9,12,15-18:4 elngtin 5-desturse 8,11,14,17-20:4 EPA 5,8,11,14,17-20:5 elngtin prstglndin PG 3 7,10,13,16,19-22:5 elngtin 4-desturse (micr-lge) 4,7,10,13,16,19-22:6 DHA 9,12,15,18,21-24:5 6-desturse 6,9,12,15,18,21-24:6 EPA = eicspentenic DHA = dcshexenic retr-cnversin DHA 4,7,10,13,16,19-22:6 W.W. Christie lipidlibrry.cs.rg 7

8 Ftty cids: methylene-interrupted duble bnds - structures, ccurrence nd bichemistry Thus, α-linlenic cid is sequentilly elngted nd desturted, with duble bnds being inserted between existing duble bnds nd the crbxyl grup, s fr s 24:6(n-3). The finl steps f wht hs been termed the Sprecher pthwy invlve retr-cnversin, i.e. remvl f the first tw crbn tms by prcess f β-xidtin, nd tke plce in the perxismes f the cell (s in the cse f the (n-6) fmily f ftty cids). All the vrius intermedites my be fund in tissues, especilly thse f fish, but eicspentenic (20:5(n-3)), dcspentenic (22:5(n-3)) nd dcshexenic (22:6(n-3)) cids tend t be by fr the mst bundnt. In humn tissues, the rtes f cnversin f α-linleic cid t lnger-chin metblites is very lw, suggesting tht high prprtin f the ltter must cme frm the diet (met, eggs nd fish) in nrml circumstnces. The rte f DHA synthesis in prticulr is s lw tht it hs been rgued tht dietry supplementtin is essentil t mintin sufficient levels in brin nd retin, lthugh vegns d nt pper t suffer ny deficiency symptms. During the nturl prcesses f turnver nd renewl f cell membrnes in retinl cells, mechnisms exist t ensure tht DHA is cnserved. The ftty cid elngse, designted ELOVL4, is respnsible fr the bisynthesis f the very-lngchin plyunsturted ftty cids f the (n-3) fmily fund in the retin. 4, 5 nd 8 Desturses hve been fund in certin micr-lge f mrine rigin (e.g. Pvlv slin), suggesting tht mre direct rute t DHA my exist in these rgnisms, including desturtin f 22:5(n-3). It hs ls been shwn tht the mmmlin 6 desturse cn perte s 8 desturse with 20:3(n-3) s substrte. With cetyl-ca s the primry precursr, the synthesis f 22:6(n-3) by the rute described bve invlves pprximtely 30 distinct enzymes nd 70 rectins. Hwever, n entirely different nd much simpler pthwy ctlysed by plyketide synthse hs been fund in mrine micrbes. The cnventinl view f plyketides is f secndry metblites cnsisting f multiple building blcks f ketide grups ( CH 2 CO ), which re synthesised by plyketide synthse. This is n enzyme system similr t the ftty cid synthse in bcteri in tht it uses cyl crrier prtein s cvlent ttchment fr chin synthesis nd prceeds in itertive cycles. Hwever, the duble bnds re intrduced during the prcess f ftty cid synthesis in cntrst t the elngtindesturtin pthwy. Much remins t be lerned f this prcess in reltin t DHA synthesis, but it is believed tht s the chin elngtes the ketnes grups re reduced t hydrxyls, nd this is fllwed by dehydrtin rectins t intrduce the duble bnds. Thus, erbic desturtin is nt required fr intrducing duble bnds int the existing cyl chin, nd it is smetimes termed n nerbic pthwy, lthugh it cn ccur under erbic cnditins. In cntrst t higher plnts nd mmmls, the nemtde Cenrhbditis elegns pssesses ll f the enzymes required fr the synthesis f 20:4(n-6) nd 20:5(n-3) ftty cids de nv, fets tht cn ls be ccmplished by the fungus, Mrtierell lpin, nd sme msses nd red lge. Essentil Ftty Acids As discussed briefly bve, linleic nd linlenic cids cnnt be synthesised in niml tissues nd must be btined frm the diet, i.e. ultimtely frm plnts. There is n bslute requirement fr these essentil ftty cids fr grwth, reprductin nd gd helth. Yung nimls deprived f these ftty cids in the diet rpidly disply dverse effects, including diminished grwth, liver nd kidney dmge, nd dermtitis; these eventully result in deth. A key bichemicl prmeter is the triene-tetrene rti, i.e. the rti f 20:3(n-9) t 20:4(n-6) ftty cids in plsm; levels greter thn 0.4 reflect essentil ftty cid deficiency. It tkes lnger fr the effects t becme pprent in lder nimls, which my hve substntil stres f essentil ftty cids in their bdy fts, but symptms will pper eventully. The effects f essentil ftty cid deficiency hve been seen in W.W. Christie lipidlibrry.cs.rg 8

9 Ftty cids: methylene-interrupted duble bnds - structures, ccurrence nd bichemistry humn infnts, n dults n prenterl nutritin r with certin genetic disrders. The bslute requirements re dependent n number f fctrs, including species nd sex (femles pper t hve higher requirement fr (n-3) ftty cids), but re usully cnsidered t be minimum f 1 t 2% fr linlete, nd smewht less fr linlente. In cntrst, the requirement fr α-linlente in fish is higher thn fr linlete. Fr sme yers it ws believed tht cts lcked Delt-6 desturse nd hd n bslute requirement fr rchidnic cid especilly in their diet, i.e. they were bligte crnivres, but this nw ppers nt t be the cse. Linlete nd linlente per se my in fct be less imprtnt thn their lnger-chin metblites in niml bilgy. It is evident tht rchidnic, eicspentenic nd dcshexenic cids ech hve distinct functins, sme f which re discussed briefly bve, which mke them essentil fr helthy niml metblism. They re precursrs f eicsnids, including prstglndins (PG 1, PG 2 nd PG 3 series), thrmbxnes, leuktrienes, nd lipxins, nd dcsnids, including reslvins nd prtectins, which hve vriety f imprtnt bilgicl prperties. In dditin, n-3 plyunsturted ftty cids my exert beneficil effects by regultry ctins in signlling prcesses, especilly in T-cells, fr exmple by mdulting the ctivities f membrne receptrs r by influencing gene trnscriptin. Plyunsturted ftty cids cnfer distinctive ttributes n the cmplex lipids tht my be required fr their functin in membrnes, nd in esterified frm they cn ls hve imprtnt bilgicl prperties. Fr exmple, rchidnic cid is n essentil cmpnent f the endcnnbinids. On the ther hnd, there re suggestins tht excessive munts f plyunsturted ftty cids in tissues, including thse f the n-3 fmily, hve the ptentil t cuse hrm. Althugh the ctul requirement fr plyunsturted ftty cids is reltively lw, generl nutritinl dvice fr the humn diet until recently ws tht they shuld cmprise substntil prt f the dily intke. Over the lst 30 yers, there hs been lrge increse in the cnsumptin f linleic cid becuse f n incresed use f vegetble ils rich in this ftty cid in the diet. By cmprisn, the intke f n-3 plyunsturted ftty cids hs been reduced becuse f reltive decrese in the cnsumptin f fish nd vegetbles. The cnsequence is tht the rti f n-6 t n-3 ftty cids in the diet is f the rder f 20:1, wheres it ws prbbly clser t 2:1 in histricl times in western cuntries. A cnsensus is emerging tht the prprtin f n-3 plyunsturted ftty cids in the diet shuld be incresed. On the ther hnd, it is recgnized tht the prpensity f ll such ftty cids fr xidtin cn led t ptentilly hrmful levels f hydrperxides in tissues, s higher reltive prprtins f dietry lete re nw ften dvised. Hwever, detiled discussin f such cntentius tpic is nt pssible here. Recmmended Reding Agbg, M.P., Mndl, M.N.A. nd Andersn, R.E. Retinl very lng-chin PUFAs: new insights frm studies n ELOVL4 prtein. J. Lipid Res., 51, (2010). Brsh, A.R. Archidnic cid s bictive mlecule. J. Clin Invest., 107, (2001). Cunnne,S.C. Prblems with essentil ftty cids: time fr new prdigm? Prg. Lipid Res., 42, (2003). Ds, U.N. Essentil ftty cids: bichemistry, physilgy nd pthlgy. Bitechnl. J., 1, (2006). Gunstne, F.D., Hrwd, J.L. nd Dijkstr, A.J. (Editrs), The Lipid Hndbk (3 rd Editin) (CRC Press, Bc Rtn) (2007). Gurr, M.I., Hrwd, J.L. nd Fryn, K. Lipid Bichemistry (5 th Editin). (Blckwells, Lndn) (2002). Hlmn, R.T. (Editr). Prgress in Lipid Reserch, Vlumes 9 (1971) nd 25 (1986). - Severl chpters. Kur, G., Cmern-Smith, D., Grg, M. nd Sinclir, A.J. Dcspentenic cid (22:5n-3): A review f its bilgicl effects. Prg. Lipid Res., 50, (2011). Meespydsuk, D. nd Qiu, X. The frnt-end desturse: structure, functin, evlutin nd bitechnlgicl use. Lipids, 47, (2012). W.W. Christie lipidlibrry.cs.rg 9

10 Ftty cids: methylene-interrupted duble bnds - structures, ccurrence nd bichemistry Nkmur, M.T. nd Nr, T.Y. Essentil ftty cid synthesis nd its regultin in mmmls. Prstglndins, Leuktrienes Essentil Ftty Acids, 68, (2003). Qiu, X. Bisynthesis f dcshexenic cid (DHA, 22:6-4,7,10,13,16,19): tw distinct pthwys. Prstglndins, Leuktrienes Essentil Ftty Acids, 68, (2003). SnGivnn, J.P. nd Chew, E.Y. The rle f meg-3 lng-chin plyunsturted ftty cids in helth nd disese f the retin. Prg. Retinl Eye Res., 24, (2005). Vnce, D.E. nd Vnce, J. (Editrs). Bichemistry f Lipids, Lipprteins nd Membrnes (5 th Editin). (Elsevier, Amsterdm) (2008) Severl chpters. Wllis, J.G., Wtts, J.L. nd Brwse, J. Plyunsturted ftty cid synthesis: wht will they think f next? Trends Bichem. Sci., 27, (2002). Wssll, S.R. nd Stillwell, W. Dcshexenic cid dmins: the ultimte nn-rft membrne dmin. Chem. Phys. Lipids, 153, (2008). Willim W. Christie Jmes Huttn Institute (nd MRS Lipid Anlysis Unit), Invergwrie, Dundee (DD2 5DA), Sctlnd Lst updted: December 5 th, 2013 W.W. Christie lipidlibrry.cs.rg 10