OTHER MEMBRANE-ASSOCIATED ISOPRENOIDS

Transcription

1 ther membrne-ssocited isoprenoids structures, biochemistry nd function TER MEMBRANE-ASSCIATED ISPRENIDS STRUCTURES, BICEMISTRY AND FUNCTIN By some definitions, ll isoprenoids from simple monoterpenes such s gerniol to complex polymers such s nturl rubber should be clssified s lipids. As discussed in my web pge Wht is lipid?, I believe this goes too fr. ere, only those isoprenoids tht hve functionl role in cellulr membrnes re discussed, including mny of the ft-soluble vitmins. Tocopherols nd tocotrienols re described in seprte document. 1. Plstoquinone A molecule tht is relted to the tocopherols, plstoquinone, is found in plnt chloroplsts nd is produced by nlogous biosynthetic pthwys to those of the tocopherols. It is lso relted structurlly to the isoprenoid lcohol solnesol. The molecule is sometimes designted plstoquinone-n (or PQ-n), where n is the number of isoprene units, which cn vry from 6 to 9. Plstoquinone hs key role in photosynthesis, by providing n electronic connection between the two photosystems, generting n electrochemicl proton grdient cross the membrne. This subsequently provides energy for the synthesis of denosine triphosphte (ATP). The reduced dihydroplstoquinone (plstoquinol) tht results trnsfers further electrons to the photosynthesis enzymes, before being re-oxidised by specific cytochrome complex. X-Ry crystllogrphy studies of photosystem II from cynobcteri show two molecules of plstoquinone forming two membrne-spnning brnches. 9 plstoquinone 2. Ubiquinone (Coenzyme Q) Plstoquinone hs obvious biosynthetic nd functionl reltionships to the ubiquinones, which re lso known s coenzyme Q or mitoquinones. These hve 2,3-dimethoxy-5-methylbenzoquinone nucleus nd side chin of six to ten isoprenoid units; the humn form illustrted hs ten units, while tht of the rt hs nine. Similrly in plnts, ubiquinones tend to hve nine or ten isoprenoid units. They re synthesised de novo in niml, plnt nd bcteril tissues, by complex sequence of rections with p-hydroxybenzoic cid s primry precursor tht is condensed with the polyprenyl unit vi specific trnsferse; this is followed by decrboxyltion, hydroxyltion nd methyltion steps, depending on the specific orgnism. C 3 C 3 C 3 10 C 3 10 ubiquinone ubiquinol W.W. Christie 1

2 ther membrne-ssocited isoprenoids structures, biochemistry nd function Becuse of their hydrophobic properties, ubiquinones re locted entirely in membrne bilyers. They re essentil components of the electron trnsport system in mitochondri, tking prt in the oxidtion of succinte or NAD vi the cytochrome system, rections tht re coupled to ATP synthesis. In the process, it is reduced to ubiquinol. Mitochondril coenzyme Q is lso implicted in the production of rective oxygen species by mechnism involving the formtion of superoxide from ubisemiquinone rdicls, nd in this wy is responsible for cusing some of the oxidtive dmge behind mny degenertive diseses. In this ction, it is pro-oxidnt. In complete contrst, in its reduced form (ubiquinol), it cts s n ntioxidnt, inhibiting lipid peroxidtion in biologicl membrnes nd serum low-density lipoproteins. It my lso protect mitochondril membrne proteins nd DNA ginst oxidtive dmge. Although it only hs one tenth of the ntioxidnt ctivity of vitmin E (α-tocopherol), it is ble to stimulte the effects of the ltter by regenerting it from its oxidized form. Dietry ubiquinone, i.e. tht in food or dietry supplements, leds to elevted levels in blood, enhncing protection ginst lipid peroxidtion with pprent beneficil effects to helth. 3. Phylloquinone (Vitmin K) Phylloquinone or 2-methyl-3-phytyl-1,4-nphthoquinone is synthesised in the chloroplsts of plnts where it is key component of the photosystem I complex nd serves s n electron cceptor. In n obvious prllel to the plstoquinones (bove), two molecules of phylloquinone form two membrne-spnning brnches, s demonstrted by X-ry crystllogrphy studies of photosystem I from cynobcteri. Both phylloquinone cofctors pss on electrons to n iron-sulfur centre in the complex. The menquinones re relted bcteril products with vrible number (4 to 10) of unsturted isoprenoid units in the til, sometimes designted MK-4 to MK-10. phylloquinone (vitmin K 1 ) menquinones (vitmin K 2 ) n where n = 3 to 9 Phylloquinone is n essentil component of the diet of nimls nd hs been termed vitmin K 1, nd it must be supplied by green plnt tissues or seed oils. In niml tissues, the only known function of vitmin K is to ct s cofctor specific to the vitmin K-dependent enzyme γ-glutmyl crboxylse nd the formtion of γ-crboxyglutmic cid, which is involved in the ctivtion of the prothrombin nd other proteins involved in blood clotting. Vitmin K must first be converted to the reduced form, vitmin K hydroquinone, which is the ctul cofctor for the enzyme, nd during the rection this is converted to vitmin K 2,3-epoxide. A further enzyme system regenertes the hydroquinone form by reduction of the epoxide so tht the former cn be re-utilized mny times. Wrfrin, the rodenticide, prevents blood clotting by interfering with vitmin K metbolism. W.W. Christie 2

3 ther membrne-ssocited isoprenoids structures, biochemistry nd function phytyl phytyl phytyl vitmin K vitmin K hydroquinone vitmin K 2,3-epoxide The menquinones lso hve vitmin K ctivity nd re termed vitmin K 2, while synthetic sturted form of this, which is used in niml feeds, is known s vitmin K 3. A deficiency in vitmin K results in inhibition of blood clotting nd cn led to hemorrhging, though this hs not been defined in humns, presumbly becuse intestinl bcteri produce sufficient for our needs. 4. Dolichol nd Polyprenols Polyisoprenoid lcohols, such s dolichols, re ubiquitous if minor components, reltive to the glycerolipids, of membrnes of most living orgnisms from bcteri to mmmls. They re hydrophobic liner polymers, consisting of up to twenty isoprene residues or hundred crbon toms (or mny more in plnts especilly), linked hed-to-til, with hydroxy group t one end (αresidue) nd hydrogen tom t the other (ω-end). In dolichols (or dihydropolyprenols), the double bond in the α-residue is hydrogented, nd this distinguishes them from the polyprenols with double bond in the α-residue. ω polyprenols t c α ω t c α dolichols (where c nd t = number of units with cis or trns double bonds, respectively) Polyisoprenoid lcohols re further differentited by the geometricl configurtion of the double bonds into three subgroups, i.e. di-trns-poly-cis, tri-trns-poly-cis, nd ll-trns. For mny yers, it ws ssumed tht polyprenols were only present in bcteri nd plnts, especilly photosynthetic tissues, while dolichols were found in mmmls or yests, but it is now known tht dolichols cn lso occur t low levels in bcteri nd plnts nd polyprenols in niml cells. Within given species, components of one chin-length my predominte, but other homologues re usully present. The chin length of the min polyisoprenoid lcohols vries from 11 isoprene units in eubcteri, to 16 or 17 in Drosophil, 15 nd 16 in yests, 19 in hmsters nd 20 in pigs nd humns. In plnts, the rnge is from 8 to 22 units, but some species of plnt hve n dditionl clss of polyprenols with up to 40 units. In tissues, polyisoprenoid lcohols cn be present in the free form, esterified with cette or ftty cids, phosphorylted or monoglycosylted phosphorylted (vrious forms), depending on species nd tissue. W.W. Christie 3

4 ther membrne-ssocited isoprenoids structures, biochemistry nd function Polyisoprenoid lcohols per se do not form bilyers in queous solution, but rther type of lmellr structure. owever, they re found in most membrnes, especilly the plsm membrne of liver cells nd the chloroplsts of plnts. Although polyprenols nd dolichols were first considered to be simply secondry metbolites, they re now known to hve importnt biologicl functions. In prticulr, glycosylted phosphopolyisoprenoid lcohols serve s crriers of oligoscchride units for trnsfer to proteins nd s glycosyl donors, i.e. substrtes for glycosyl trnsferses, for the biosynthesis of glycns in similr mnner to the cytosolic sugr nucleotides. They differ from the ltter in their intrcellulr loction, with the lipid portion in the membrne of the endoplsmic reticulum nd the oligoscchride portion specificlly locted either on the cytosolic or lumenl fce of the membrne. Biosynthesis of the bsic building block of dolichols, i.e. isopentenyl diphosphte, follows either the mevlonte pthwy discussed in reltion to cholesterol biosynthesis elsewhere on this site, or more recently described methylerythritol phosphte pthwy. Subsequent formtion of the liner prenyl chin is ccomplished by prenyl trnsferses tht ctlyse the condenstion of isopentenyl diphosphte nd the llylic prenyl diphosphte. 5. Retinol (Vitmin A) The term vitmin A is used to denote retinol or ll-trns-retinol nd fmily of biologiclly ctive retinoids derived from this. These re only found in niml tissues, where they essentil to innumerble biochemicl processes. owever, the biosynthetic precursors of these compounds re plnt crotenoids (provitmin A) of which β-crotene is most efficient, nd occurs in the green prts of plnts nd seed oils. In the humn diet, plnt sources tend to be less importnt thn those from diry products, met, fish oils nd mrgrine. In the U.K., for exmple, ll mrgrine must be supplemented with the sme level of vitmin A (synthetic retinol or β-crotene) s is found in butter. β-crotene retinl retinoic cid retinol C(C 2 ) 14 C 3 retinyl plmitte W.W. Christie 4

5 ther membrne-ssocited isoprenoids structures, biochemistry nd function Retinol is the min form of the vitmin tht is trnsported in blood, bound minly to retinol-binding protein with some in the lipoprotein complexes, while retinol esters (principlly retinyl plmitte) is the min storge form, occurring chiefly but not exclusively in the liver. A reltively smll proportion of the cellulr retinoids is locted in membrnes. The biosynthesis of crotenoids hs much in common with tht of cholesterol (see the pproprite web pge), but this is too specilized topic for discussion here. In nimls, dietry β-crotene is subjected to oxidtive clevge t its centre to yield two molecules of ll-trns-retinl, which is reversibly reduced to retinol nd then esterified to form retinyl plmitte. Activtion of the retinol pthwy, involves first mobiliztion of the ester, followed by hydrolysis nd reversible oxidtion of retinol to retinl. The lst is then oxidized irreversibly to retinoic cid. Both retinol nd retinoic cid re precursors of number of metbolites (retinoids), which re required for specific purposes in tissues, by vrious desturtion, hydroxyltion nd oxidtion rections. It hs long been know tht retinoids re essentil for vision, nd there is good pprecition of how this works t the moleculr level (see below). It is now relized tht they lso hve essentil roles in growth nd development, reproduction nd resistnce to infection. They re prticulrly importnt for the function of epithelil cells in the digestive trct, lungs, nervous system, immune system, skin nd bone t ll stges of life. For exmple, they re required for the regenertion of dmged tissues. They pper to hve some potentil s chemo-preventive gents for cncer nd for the tretment of skin diseses such s cne. More recently, it hs been recognized tht mny of the retinol metbolites function s lignds to ctivte specific trnscription fctors for prticulr receptors in the nucleus of the cell, nd thus they control gene expression. Retinoic cid is especilly importnt in this context. It hs lso become evident tht mny of the functions of retinoids re medited vi the ction of specific binding proteins, which control their metbolism in vivo by reducing the effective or free retinoid concentrtions, by protecting them from unwnted chemicl ttck, nd by presenting them to enzyme systems in n pproprite conformtion. For exmple, specific retinol-binding protein secreted by dipose tissue (RPB4) is involved in the development of insulin resistnce nd type 2 dibetes, possibly by ffecting glucose utiliztion by muscle tissue. Vitmin A deficiency in children nd dult ptients is usully ccompnied by impirment of the immune system, leding to greter susceptibility to infection nd n incresed mortlity rte. Thus it is not lwys esy to distinguish between these effects nd primry defects of retinoid signlling. owever, one of the primry effects of vitmin A deficiency in mlnourished children, nd seen too often in the underdeveloped world, is blindness. This is doubly trgic in tht it is so esily prevented. Retinl rod nd cone cells in the eye contin membrnous vesicles tht serve s light receptors. Roughly hlf of the proteins in these vesicles consist of the protein conjugte, rhodopsin, which consists of 11-cis-retinl C protein opsin nd 11-cis-retinl. When this is ctivted by light, the cis-double bond is isomerized non-enzymticlly to the 11-trns form with chnge of conformtion tht in turn ffects the permebility of the membrne nd influences clcium trnsport. This results in further moleculr chnges tht culminte in the relese of opsin nd lltrns-retinl, which re the trigger tht sets off the nerve impulse so the light is perceived by the brin. The ll-trns-retinl is converted bck to 11-cis-retinl by vrious enzymtic rections, so tht the rhodopsin cn be regenerted. Retinyl-β-D-glucoside, retinyl-β-d-glucuronide, nd retinoyl-β-d-glucuronide re nturlly occurring nd biologiclly ctive metbolites of vitmin A, which re found in fish nd mmmls. Indeed, the W.W. Christie 5

6 ther membrne-ssocited isoprenoids structures, biochemistry nd function lst hs similr ctivity to ll-trns-retinoic cid without ny of the unwnted side effects in some circumstnces. In ddition, retinoic cid cn undergo metbolism into 4-hydroxy-, 4-oxo- nd 18- hydroxy-retinoic cids, s prt of the process of degrdtion nd elimintion. 6. Lipid-Linked Intermedites in Peptidoglycn Synthesis Undecprenyl phosphte ( C 55 isoprenoid), lso referred to s bctoprenol, is lipid intermedite tht is essentil for the biosynthesis of peptidoglycn nd mny other cell-wll polyscchrides, nd for N-linked protein glycosyltion in prokryotes. It is required for the synthesis nd trnsport of hydrophilic GlcNAc-MurNAc-peptide monomers cross the cytoplsmic membrne to externl sites for polymer formtion. trns cis cis P trns 7 undecprenyl phosphte Undecprenyl diphosphte-murnac-pentpeptide-glcnac, sometimes termed lipid II, is the lst significnt lipid intermedite in this process, nd it hs only recently been identified s norml constituent in vivo of the membrnes of Escherichi coli, by the ppliction of modern mss spectrometric methods. Recommended Reding o Booth, S.L. nd Sltzmn, E. Vitmin K: structure nd function. In: Encyclopedi of Life Sciences. John Wiley & Sons, Ltd: Chichester (doi: /npg.els ) (2001). o Bouhss, A., Trunkfield, A.E., Bugg, T.D.. nd Mengin-Lecreulx, D. The biosynthesis of peptidoglycn lipid-linked intermedites. FEMS Microbiol. Rev., 32, (2008). o DellPenn, D. nd Pogson, B.J. Vitmin synthesis in plnts: tocopherols nd crotenoids. Annu. Rev. Plnt Biol., 57, (2006). o Jmes, A.M., Smith, R.A.J. nd Murphy, M.P. Antioxidnt nd prooxidnt properties of mitochondril Coenzyme Q. Arch. Biochem. Biophys., 423, (2004). o Krg, S.S. The importnce of being dolichol. Biochem. Biophys. Res. Commun., 243, 1-5 (1998). o Meissburger, B. nd Wolfrum, C. The role of retinoids nd their receptors in metbolic disorders. Eur. J. Lipid Sci. Technol., 110, (2008). o Swiezewsk, E. nd Dnikiewicz, W. Polyisoprenoids: structure, biosynthesis nd function. Prog. Lipid Res., 44, (2005). o Turunen, M., lsson, J. nd Dllner, G. Metbolism nd function of coenzyme Q. Biochim. Biophys. Act, 1660, (2004). W.W. Christie Scottish Crop Reserch Institute (nd Mylnefield Lipid Anlysis), Invergowrie, Dundee (DD2 5DA), Scotlnd Lst updted: 14/3/2008 W.W. Christie 6