Polyprenol biosynthesis

Little is known as to the biosynthesis and metabolism of plant dolichols. Nevertheless, this is an interesting field if the variety of polyprenols synthesized by plants (see Table I and Scheme 1), as compared with animals, is considered. The early knowledge on the stereochemistry of E, Z-polyprenol biosynthesis was obtained by Gough and Hemming63 with a plant system. They found that the 4-5 hydrogen atom of mevalonate is retained when a Z- double bond is formed, whereas this hydrogen atom is lost in the biosynthesis of an -double bond. The same authors found similar results for rat-liver dolichol.64 With this technique, [3H]dolichol was found in rat-liver mitochondria when the animals were injected with65 4-(S)-[3H]meval-... 

Long-chain polyisoprenoid. molecules with a terminal alcohol moiety are called, polyprenols. The dolichols, one class of polyprenols (Figure 8.18), consist of 16 to 22 isoprene units and, in the form of dolichyl phosphates, function to carry carbohydrate units in the biosynthesis of glycoproteins in animals. Polyprenyl groups serve to anchor certain proteins to biological membranes (discussed in Chapter 9). 

C. Nucleoside Diphosphate Sugars.—A polyprenol phosphate containing eleven isoprene units is involved in the biosynthesis of various bacterial cell-wall components.As mentioned in last year s Report, another isoprenoid phosphate, dolichol monophosphate (40), is an intermediate in sugar... 

Biosynthesis.—Ubiquinone. The identification of 3,4-dihydroxyhexaprenylben-zoate (162) in a Saccharomyces cerevisiae mutant strain that cannot synthesize ubiquinone suggests that (162) may be an intermediate in ubiquinone-6 biosynthesis in eukaryotes, in contrast to the pathway via 2-polyprenylphenol which operates in prokaryotes. In mammalian systems alternative routes have been discussed for ubiquinone biosynthesis in rats." Some properties of mitochondrial 4-hydroxybenzoate-polyprenol transferase have been described."" ... 

The structures of polyprenyl diphosphate-linked intermediates of Salmonella O-specific-polysaccharide biosynthesis were confirmed by chemical synthesis of their analogs derived from the plant polyprenols ficaprenol and moraprenol (structurally related to bacterial polyprenol57) with the following study of their behavior as substrates of enzymic reactions. Synthetic polyprenyl a-D-galactopyranosyl diphosphate291,292 was found to serve as an effective acceptor for the transfer of L-rhamnosyl groups.293"295 Two synthetic, isomeric disaccharide derivatives,292 13 and296 14, were tested as acceptors for enzymic D-mannosyl transfer from GDP-Man, but only the former was found to be an efficient substrate.294... 

Grange and Adair73 isolated 2,3-dehydrodolichyl phosphate from in vitro studies on hen oviduct. It may be derived from 2,3-dehydrodolichyl diphosphate, a likely intermediate in the biosynthesis of dolichyl phosphate. Many questions still remain unanswered, such as is the substrate for the a-isoprene reductase, the diphosphate or the monophosphate of 2,3-dehy-drodolichol Are the unsaturated polyprenols a reserve pool for the synthesis of dolichol in plants What is the function of unsaturated, plant polyprenols How is the synthesis of saturated and unsaturated polyprenols regulated ... 

The )8-(1 2)- and a-(1 5)-linked arabinose residues are incorporated into the polymer from the activated polyprenyl sugar phosphate 10, which is in turn synthesized from glucose via 5-phosphoribose pyrophosphate (pRpp) [46-48]. Elongation of the polymer chain is believed to involve a family of arabinosyltransferases (AraT s) that recognize both 10 and arabinofuranoside-based acceptors of differing structures (Fig. 5) [18,19,49,50]. In AG biosynthesis, the entire polysaccharide appears to be assembled as a polyprenol diphosphate intermediate, which is transferred to peptidoglycan prior to the addition of the mycolate esters [18]. In LAM biogenesis, the arabinan portion is believed to be synthesized as a polyprenol phosphate that is transferred to lipomannan [51]. 

The chemical structure of naturally occurring ais polyisoprenes was determined by 13C NMR spectroscopy using acyclic terpenes and polyprenols as model compounds. The arrangement of the isoprene units along the polymer chain was estimated to be in the order dimethylallyl terminal unit, three trans units, a long block of ais units, and ais isoprenyl terminal unit. This result demonstrates that the biosynthesis of cis-polyisoprenes in higher plants starts from trans,trans,trarcs-geranylgeranyl pyrophosphate. ... 

This paper describes the structural analysis of naturally occurring ois-1,4 polyisoprenes using 13C NMR spectroscopy. First, the structural characterization of polyprenols, which are linear isoprenoid compounds containing 30 to 100 carbons, was carried out on the basis of information obtained from acyclic terpenes having various ois and trans isoprene units as model compounds. This method was also applied to the structural analysis of polyisoprenes. The elucidation of the structure of the end groups and the arrangement of isoprene units provides information on the mechanism of the biosynthesis of polyprenyl compounds in nature. 

The polyprenols composed of trans and cis isoprene units isolated so far have been classified into two types the ficaprenoltype and the betulaprenol-type, containing three and two internal trans units, respectively (12). The findings described above suggest that trans,trans,tra s-geranylgeranyl pyrophosphate or trans,trans-farnesyl pyrophosphate acts as an initiator of the biosynthesis of polyprenols. 

Polyterpenoids.— C N.m.r. has been used to investigate the structure of the C55 polyprenol moraprenol-11 (190) from leaves of Moms alba. The main component has the trans-trans-trans-cis-cis-cis-cis-cis-cis-cis-OH configuration. The monophosphate of this compound was prepared in 34% yield by treatment with o-phenylenephosphorochloridate. Biosynthetic studies have provided evidence for the formation of 2,3-dehydrodolichyl phosphate (191) as an intermediate in dolichyl phosphate (192) biosynthesis. Most of the members of a series of C2S—C40 acyclic hydrocarbons obtained from crude oil have isoprenoid or degraded isoprenoid structures. The mokupalides from a marine sponge have been shown to be hexaprenoids with structures (193)—(195). ... 

Polyterpenoids.—A general review has been published of the structures, occurrence, biosynthesis, and metabolism of polyprenols and isoprenylated quin-ones. A diol from insect wax has been identified by spectroscopic methods as the C25 isoprenoid to-hydroxygeranylfarnesol (189). CN.m.r. has shown... 

Heifetz, A. Elbein, A.D. (1977) Biosynthesis of Man-GlcNAc-GlcNac-pyrophosphoryl-polyprenol by a Solubilised Enzyme from Aorta , Biochemical and Biophysical Research Communications, 75, 20-8... 

Biosynthesis of Saccharomyces cerevisiae LK 2G12 Mannan , FEBS Letters, 14,109-13 Sentendreu, R. Lampen, J.O. (1972) Biosynthesis of Mannan in Saccharomyces cerevisiae. Isolation of a lipid Intermediate and its Identification as a Mannosyl-1-phosphoryl Polyprenol , FEBS Letters, 27, 331-4 Sharma, C.B., Babczinski, P., Lehle, L. Tanner, W. (1974) The Role of Dolichol-monophosphate in Glycoprotein Biosynthesis in Saccharomyces cerevisiad, European Journal of Biochemistry, 46, 35-41... 

The biosynthesis of the mannan inner core involves dolichol pyrophosphate derivatives containing JV-acetyl glucosamine and several mannose residues [38]. The participation of the polyprenol (dolichol) in the biosynthesis of the mannan inner core in yeast is analagous to its role in animal tissues as a mechanism for the glycosylation of proteins. 

The levels of other isoprenoids are also stimulated, including ubiquinones and polyprenols, resulting in an overall tenfold increase in isoprenoids under some conditions (lO). Amongst these are the mating type—specific trisporate precursors (see Fig. 3), and this response must be central to the switch-on of trisporic acid biosynthesis during mating. 

Dolichol is related to vitamin A (10.66a), the phosphate ester of which may also be involved in glycosyl transfer reactions in the body (Chapter 11). Polyprenol pyrophosphates are involved in the biosynthesis of rubber, gutta-percha and other terpenes (Chapter 11.5). 

There is now a great deal of evidence that liposaccharide intermediates are involved in some biosyntheses of polysaccharides in animals and bacteria. This is an alternative to the UDP-sugar process (11.60) and utilises various nucleoside diphosphate sugars together with a polyprenol phosphate. The presence of a long hydrocarbon chain in the latter is believed to facilitate biosynthesis in the hydrophobic regions of membranes. 

The role of undecaprenyl phosphate (C55, allylic) as a carrier of glycosyl units in the biosynthesis of bacterial cells walls is well established. Dolichyl phosphate plays a similar role in the synthesis of glycoproteins in animal systems. Evidence that prenyl lipids serve as glycosyl carriers in the biosynthesis of glycoproteins in plants is accumulating rapidly (Pont Lezica et al., 1976 Delmer al., 1978 Erickson et al., 1978). Several authors have recently reviewed the literature on the role of polyprenols as glycosyl carriers in plants (Hemming, 1978 Pont Lezica, 1979 Elbein, 1979). 

Threlfall, D. R. Polyprenols and terpenoid quinones and chromanols. In Encyclopedia of Plant Physiology, New Series, Vol. 8 Secondary Plant Products (E. A. Bell, B. V. Charlwood, eds.), pp. 288-308. Springer, Berlin-Heidelberg-New York 1980 Threlfall, D. R., Whistance, G. R. Biosynthesis of isoprenoid quinones and chromanols. In Aspects of Terpenoid Chemistry and Biochemistry (T. W. Goodwin, ed.), pp. 357-404. Academic Press, London 1971... 

In plant tissues two major forms of polyprenols are found, e.g. free alcohols and esters with fatty acids. In some species one form is highly dominating. Similarly in animal tissues dolichols and dolichyl esters were described, accompanied by usually small amounts of dolichyl phosphate. Biological role of this latter compound is well established. Dolichyl phosphate is involved as cofactor in biosynthesis of glycoproteins and GPI-anchored proteins [3]. Biological role of free alcohol and its acyl ester has not been defined yet. As the components of biological membranes these compounds modulate membrane properties. Dolichol increases fluidity and permeability and decreases the stability of model membranes [4]. Experiments with polyprenols point to the same direction polyprenols and polyprenyl phosphates increases the fluidity and permeability of model membranes [5], Both polyprenols and dolichols could also serve as a reserve isoprenoid pool utilized by corresponding kinases. 

The participation of polyprenol sugar phosphates as intermediates in the biosynthesis of several types of complex carbohydrate has been clearly established in bacteria (for a review see ref. 11). Tanner in 1969< > presented the first evidence of the possible participation of lipid carriers in yeast. This was confirmed by us and the carrier was found to be a phosphodiester of mannose and an isoprenoid alcohol.Finally, Jung and Tanner purified a lipid which was able to accept mannose from GDP-mannose when added exogenously to a particulate preparation. This lipid was characterized as a dolichol phosphate. 

Sentandreu, R. and Lampen, J. O. (1972) Biosynthesis of mannan in Saccharomyces cerevisiae. Isolation of a lipid intermediate and its identification as a mannosyl-l-phosphoryl-polyprenol. FEBS Lett. 27, 331-334. 

The biosynthesis and structure of polyprenol-Iinked sugars, and the role of such sugars, retinol phosphate, and vitamin K in the synthesis of glycoproteins, have been reviewed. Information on proteins that serve as acceptors and the role of glycosyl-transfer reactions involving lipid-linked sugars are also discussed. 

Other appropriate points of action for drugs inhibiting cholesterol biosynthesis are between mevalonic acid and squalene. The presence of hepatic catabolic pathways for polyprenol precursors of squalene eventually accumulated has been detected. Several drugs have been shown to act on cholestnogeneds at these levels (vanadium salts, sesquiterpenes, benzmalacene, SKF-525-At. sulphonylureas) but they have not found, so far, clinical applications. 

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