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The Stereochemistry of Betulaprenol Biosynthesis

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The Stereochemistry of Betulaprenol Biosynthesis Biochem. J. (1970) 117, 309-317 309 Printed in Great Britain The Stereochemistry of Betulaprenol Biosynthesis BY DOREEN P. GOUGH* AND F. W. HEMMING Department of Biochemi8try, Univer8ity of Liverpool, Liverpool L69 3BX, U.K. (Received 1 December 1969) By using stereospecifically double-labelled radioactive mevalonates it was shown that betulaprenols-6 to -9, found in the woody tissue of Betula verruco8a, each contain three biogenetically trane-isoprene residues and that the remaining residues are biogenetically ci8. The results obtained with these radioactive mevalon- ates also indicated that the activity of isopentenyl pyrophosphate isomerase is low relative to the activity ofprenyltransferase in this woody tissue. The incorporation of radioactive farnesyl pyrophosphate and radioactive geranylnerol and the lack of incorporation of radioactive geranylgeraniol into betulaprenols-6 to -9 demon- strated that they are formed by the ci8-additions of isoprene residues to all-tran8- farnesyl pyrophosphate. The woody tissue of Betula verrucoWa (silver biogenetically trans, and the chemically ciw residues birch) contains betulaprenols-6, -7, -8 and -9. It has to be biogenetically cis. It would also require the been shown that in each polyprenol two of the in- internal trans residues to be at the co-end of the ternal isoprene residues are chemically trans, and molecule. the other internal residues and the a-residue are The biosynthesis of polyprenols involves the iso- chemically ciw (Lindgren, 1965; Wellburn & Hem- merization of isopentenyl pyrophosphate to di- ming, 1966). These polyprenols are present in methylallyl pyrophosphate and the condensation of woody tissue mainly as their fatty acid esters at isopentenyl pyrophosphate with dimethylallyl concentrations of up to 1 .5g/kg of tissue (Lindgren, pyrophosphate or its higher isoprenologues. In 1965). They are also found in the non-esterified each of these steps a C-C bond is formed, accom- free alcohol form in the leaf tissue of B. verruco8a, panied by the loss of a hydrogen atom from C-2 of where they reach concentrations of 10mg/kg of isopentenyl pyrophosphate. The hydrogen atom tissue (Wellburn & Hemming, 1966). lost is one of two originally attached to C-4 of The leaftissue also contains c8-tran8-polyprenols mevalonic acid. By using [2-14C,(4R)-4-3Hj]- and with chain lengths of ten to 13 isoprene residues. In [2-14C,(4S)-4-3Hj]-mevalonate as substrates, the each of these betulaprenols-10 to -13 it has been stereochemistry of this hydrogen elimination has shown that three internal residues are chemically been studied in several systems. Work on the bio- tranm and the other internal residues and the a- synthesis oftran8-tran8-farnesyl pyrophosphate and residue are chemically ci8. These are present in all-tran8-squalene with a rat liver preparation their free alcohol form at concentrations of up to (Cornforth, Cornforth, Donninger & Popjak, 1965), 134mg/kg of leaf tissue, and have also been shown of squalene and phytoene with carrot-root prepara- to be present, to a lesser extent, as the free alcohols tions (Goodwin & Williams, 1965), of squalene and in the woody tissue at concentrations reaching ubiquinone in Aqpergillu8 fumigatu8 Fresenius 19mg/kg of tissue (Wellburn & Hemming, 1966). (Stone & Hemming, 1967) and of squalene and It has been suggested that the betulaprenols-6 to phytol in green leaves (Wellburn, Stone & Hem- -9 are probably formed from trans-trans-farnesyl ming, 1966) shows that all of the 4S-tritium is lost pyrophosphate by ci8-additions ofisoprene residues, and all of the 4R-tritium is retained. Hence, in the and that the leaf polyprenols- 10 to -13 are probably biogenesis of all-trans-polyisoprenoid compounds formed from all-tran8-geranylgeranyl pyrophos- the 4-pro-R-hydrogen of mevalonic acid is retained phate in a similar manner (Wellburn & Hemming, and the 4-pro-S-hydrogen is eliminated. In the 1966). Such a mechanism would require the internal biosynthesis of poly-c8-rubber, the 4R-tritium is chemically tran8 residues and the co-residue to be lost and the 4S-tritium retained (Archer et al. 1965). * Present address: Muscular Dystrophy Laboratory, Hence, although the evidence is limited, it seems Medical Centre for Neurosurgery and Neurology, Smeth- that in the biogenesis of all-ci8-polyisoprenoid com- wick, Worcs., U.K. pounds the 4-pro-R-hydrogen of mevalonic acid is 310 D. P. GOUGH AND F. W. HEMMING 1970 lost and the 4-pro-S-hydrogen is retained. The Popjak, 1968). The co-residue of polyisoprenoid generalization can thus be made that in the bio- chains always appears to be biogenetically tran8. genesis oftran8-isoprene units the 4-pro-R-hydrogen Thus 4S-tritiated mevalonic acid gives rise to 2R- of mevalonic acid is retained and the 4-pro-S- tritiated isopentenyl pyrophosphate, which can be hydrogen eliminated, and in the biogenesis of ci8- isomerized to dimethylallyl pyrophosphate with the isoprene units the 4-pro-R-hydrogen is eliminated stereospecific removal of tritium. This dimethyl- and the 4-pro-S-hydrogen is retained. allyl pyrophosphate is the source of the biogenetic- With polyisoprenoid compounds of mixed stereo- ally trans co-residues (Scheme la). If step (1) is chemistry the evidence is not quite so conclusive. readily reversible, then isopentenyl pyrophosphate By using [2-14C,(4R)-4-3Hj]mevalonate, the pres- is formed that is devoid of tritium. Hence, if step ence of four biogenetically tran8 residues in the (1) is much more rapid than step (2), the 3H/14C hexahydropolyprenols of A. fumigatus has been ratios from incubations with [2-14C,(4S)-4-3Hj]- shown. However, the 3H/14C ratios in the hexa- mevalonate will be lower than expected. It is hydropolyprenols biosynthesized from [2-14C,(4S)- notable that in the latex ofHevea bra89ilien8si, where 4-3H,]mevalonate were about 40% lower than ex- the 3H/14C ratios obtained by the incorporation of pected (Stone & Hemming, 1967). This loss of 4S- [2-_4C,(4S)-4-3HI]mevalonate into poly-cis-rubber tritium is probably accounted for by the presence of were as expected (Archer et al. 1965), the activity of a highly active isopentenyl pyrophosphate iso- isopentenyl pyrophosphate isomerase has been re- merase. The isomerization of isopentenyl pyro- ported to be very low (Archer, Audley, Cockbain & phosphate to dimethylallyl pyrophosphate is re- McSweeney, 1963; Archer & Audley, 1967). This versible (Agranoff, Eggerer, Henning & Lynen, would explain why there was no loss of tritium from 1960; Shah, Cleland & Porter, 1965; Holloway & 4S-tritiated mevalonate in this system. The pres- DMAPP CH3 (a) H 4S-MVA \ " %C/CH2*°-P206H3 Ho H 'T' 'H' \(-1) 011 IPP IP Hs tC\C37CH2.0P206H3/ HNI C\ CH2*.0P206113 X 'H' HHF T T H 'H' HH H trans-Residues c-Residues trans-Residues cis-Residues cis-Residues OCH3 I-H2C7Cu,Zc7HI L CHz-J~~~~~~~~ Scheme 1. (a) Incorporation of 3H from [(4S)-4-3H]-mevalonic acid (MVA) into isoprenoid residues. Abbreviations: DMAPP, dimethylallyl pyrophosphate; IPP, isopentenyl pyrophosphate. Enzymes: 1, IPP isomerase; 2, prenyltransferase. Vol. 117 BETULAPRENOL BIOSYNTHESIS 311 DMAPP CH3 (b) l\0 I , 4R-MVA sCH2.0;P206H3 H T \ A!T W~ 'H' (i) IPP IPP CH3 "II-* CH3 ,C\ /CH2.O.P206H3 HN /CH2.O.P2O6H3 HO0' c N C. HV' 'H' RH' T 'H' H trans-Residues w-Residues trans-Residues cii-Residues ci8-Residues CHi Scheme 1. (b) Incorporation of 3H from [(4R)-4-3H]-mevalonic acid (MVA) into isoprenoid residues. ence of a highly active isopentenyl pyrophosphate betulaprenols are, in fact, biogenetically tranm and isomerase does not affect the 3H/"4C ratios obtained the chemically ciw residues in these polyprenols are from incubations with [2-_4C,(4R)-4-3Hj]mevalon- biogenetically c8, and whether or not the activity of ate. 4R-Tritiated mevalonic acid gives rise to 2S- isopentenyl pyrophosphate isomerase relative to tritiated isopentenyl pyrophosphate, which can then the activity of prenyltransferase is high in Betula be isomerized to dimethylallyl pyrophosphate with verrucosa. In addition, the incorporation of [14C]- the stereospecific retention of tritium (Scheme lb). farnesyl pyrophosphate and of ["4C]geranylgeraniol Thus to-residues formed from 4R-tritiated meva- and [O4C]geranylnerol into the betulaprenols has Ionic acid will possess tritium, showing them to be also been studied. The results are reported in this biogenetically trans. Isomerization of this tritiated paper. Some of the results have been reported dimethylallyl pyrophosphate back to isopentenyl previously (Gough & Hemming, 1967). pyrophosphate results in the re-formation of 2S- tritiated isopentenyl pyrophosphate. Hence it MATERIALS AND METHODS seems that the 3H/14C ratios obtained from incuba- tions with these double-labelled mevalonates can Incorporation ofthe radioactive mevalonates. [2-14C,(4R)- provide information about the relative activities of 4_3Hflmevalonate and [2-14C,(4S)-4-3Hj]mevalonate were isopentenyl pyrophosphate isomerase (EC 5.3.3.2) prepared as described by Wellburn et al. (1966) from mix- and prenyltransferase (EC 2.5.1.1), in addition to tures of original specific radioactivities as follows: providing information about the stereochemistry of 3R-[(4R)-4_3H1]- and 3S-[(4S)-4-3Hl]-mevalonic acid lac. tone, 134mCi/mmol; 3R-[(4S)-4-3H,]- and 3S-[(4R)-4- biosynthesis of isoprene residues. 3H,]-mevalonic acid lactone llSmCi/mmol; 3R,S-[2-14C]- The general availability of [2-14C,(4R)-4-3H1]- mevalonic acid lactone, 5.03mCi/mmol. and [2-14C,(4S)-4-3Hj]-mevalonate provided an op- Two terminal twigs of B. verruco8a, about 9in long and portunity to determine whether the chemically carrying 8-12 leaves, were each allowed to take up either tran8-isoprene residues and the co-residues of the [2 -14C,(4R) -4 _3Hj] - or [2 _4C,(4S) -4-3H,] - mevalonate 312 D. P. GOUGH AND F. W. HEMMING 1970 (5,ACi of 14C in approx. 0.5ml of 60mm-K2HPO4-KH2PO4 (Woelm, Eschwege, Germany; Brockmann grade III, buffer, pH 7.4) by transpiration over 2-4h.
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