Biogenesis

The biogenesis of the quinoline alkaloids found in the Rutaceae has been the subject of considerable speculation some earlier suggestions, concerned with the biogenesis of the simple 2-aryl- and 2-alkyl-quinolines, such as the angostura alkaloids, were discussed in Volume III, Chapter 17. 

It has generally been considered that the quinoline alkaloids of the Rutaceae, together with the acridine and quinazoline alkaloids which often occur alongside them, are all derived from an anthranilic acid 

Several suggestions were put forward by Robinson for the origin of the furan ring in the furoquinolines it could be the residue of the tryptophan side chain existing in the intermediate XCVIII it could be formed by 

Such analogies clearly lead to the supposition that the unsubstituted furan ring may arise by the fission of a 3-carbon fragment from the cyclized isopentane unit this idea is far from new in the furocoumarin field 158), but its applicability to the furoquinoline series became obvious only after the structures of alkaloids such as orixine, lunacrine, and balfourodine had been established 14). 

Alternative suggestions for the construction of the furan ring have been made by Wenkert 154), who invokes a condensation of anthranilic acid with erythrose, and by Ghosal 159), who utilizes anthranilic acid and ornithine as precursors (see p. 262), 

For these experiments to be successful, it is imperative that the labeled precursors be fed directly to the latex in the poppy capsules, otherwise the added labeled dopa fails to penetrate to the site of the appropriate aminotransferase 

Working with Litsea glutinosa (Lauraceae), and concentrating on the biosynthesis of reticuline, Bhakuni and co-workers have shown that dopa and dopamine contribute only to the formation of the phenethylamine portion of reticuline. The benzylic portion is biosynthesized from 3,4-dihydroxyphenyl-pyruvic acid not derived from dopa. Tyrosine, 4-hydroxy-, and 3,4-dihydroxy-phenylpyruvic acid all participate in the formation of both halves of the molecule. Norlaudanosoline carboxylic acid, norlaudanosoline, and didehydronor-laudanosoline are intermediates in the biosynthetic sequence 0-methylation precedes W-methylation.  

It has been claimed that norlaudanosoline is present in nanogram quantities in rat brain following chronic administration of (—)-dopa. The laboratory synthesis of papaverine derivatives specifically labeled with has been discussed.  

The four benzylisoquinolines of clinical interest are papaverine, used as an antispasmodic and peripheral vasodilator dioxyline, also a peripheral and coronary vasodilator the closely related ethaverine, which is another smooth muscle relaxant and trimetoquinol, which is a bronchodilator. Several new analogs of these compounds have been screened for pharmacological activity.  

Pyridones, such as 39 and 40, which bear a structural relationship to papaverine, have shown enhanced activity and/or duration of peripheral vasodilator activity in dogs. (- )-Trimetoquinol has more potent j8-adrenergic activity than its enantiomer in a variety of systems. The intact tetrahydro-isoquinoline nucleus appears to be necessary for the j8-adrenoceptor action of this synthetic diphenolic tetrahydrobenzylisoquinoline.  

Role of Perilipins In LD, accumulation of perilipins and TAG occurs roughly in parallel. When FA synfhesis was inhibited, fhe concentration of TAG decreased by 90% and correspondingly fhe amount of perilipin dropped [153]. The availability of only a small amount of TAG may cause formation of small LD with insufficient surface space for fhe association of perilipin. Decreased synthesis of FA resulting in libera- 

Growth Adipocyte differentiation in WAT involves the coalescence of small nascent LD to form tlie one or more large LD found in mature cells. By contrast, most other cell types contain numerous smaller LD (see above). Franke and co- 

The LD from fhe cell-free system, like those from 3T3-L1 cells, contained TAG, DAG, phosphatidylchohne, phosphatidylethanolamine, and phosphatidylserine 

TAG mobihzation by hpolysis as a strictly regulated process has been known since the early 1960s, when it was estabhshed that fast-acting hormones such as ACTH and epinephrine increased hpolysis [219, 220], and that insuhn counteracted this activation [221-223]. It was soon recognized that cAMP was involved in the regulation of the catecholamine-sensitive lipolytic activity in adipose tissue 

The synthesis of mitochondrial membranes in which the synthesis of both outer and inner compartments is linked closely to the cell cycle and 

Differentiation of the organelle for respiratory chain phosphorylation, requiring coordinated control of both nuclear and mitochondrial genes. This is independent of cell growth and division. 

The supply of lipids for mitochondrial membrane biosynthesis depends largely on lipids synthesized elsewhere in the cell, especially the endoplasmic reticulum. However, one major lipid component of the inner mitochondrial membrane, cardiolipin (diphosphatidylglycerol), is synthesized within the mitochondria. 

One disorder of mitochondrial transport in humans is due to a failure to transport the methylmalonyl-CoA-mutase precursor protein. The mutation responsible for this disorder affects the signal sequence region. An- 

Alkaloids from colonial zoanthids such as zoanthamine, zoanthamide, 28-deoxyzoanthenamine, and others form a new class of alkaloids of unknown biosynthetic origin, although some structural features suggest a triterpenoid origin (20-23). 

Pettit et al., have proposed a biogenetic pathway for the dimeric pyrazine-containing steroidal alkaloids, the cephalostatins isolated from the marine worm Cephalodiscus gilchristi and the tunicate Ritterella tokioka. These alkaloids contain at least 13 fused rings, which constitutes the largest such system known in marine animals. 

Plakinamine A (1), an alkaloid isolated from an unidentified species of Plakina, was found to inhibit the growth of Staphylococcus aureus and 

Candida albicans at concentrations of 25 /zg/disk and 10 /ug/disk, respectively. The hydrochloride salt of plakinamine B (2) also exhibited antibacterial activity at a level of 10 jug/disk and 2 /ug/disk against S. aureus and C. albicans, respectively (18). 

Lokysterolamine A (3) exhibited in vitro cytotoxic activity against the mouse lymphoid leukemia (P-388), human lung carcinoma (A-549), human melanoma (MEL-28), and human colon adenocarcinoma (HT-29) cell lines. Owing to its structural similarity with plakinamines A and B, the alkaloid also exhibited antibacterial activity against Bacillus subtilis and C. albicans. In addition, it showed moderate immunomodulatory activity (LcV/MLR 187) (19). 

The simple basis for the biosynthesis of alkaloids in the plant cell is that a few common amino acids can be converted simply into reactive intermediates which may then condense spontaneously in variants of the Mannich reaction to yield, virtually at a stroke, the fully elaborated nuclei of the alkaloids. More detailed accounts of the biogenetic concept 

That the major condensation step of aldehyde CCLXVIII and tryp-tamine can in fact occur under physiological conditions has been amply demonstrated by Hahn (351) in a striking physiological synthesis of a base with the yohimbine skeleton (CCLXX). Hahn s demonstration of spontaneous condensation at the indole a-position, however, casts doubt on the facility of the jS-condensation required for the Strychnos alkaloids and leads us to consider a variation of the scheme in which the a-position is oxidized first to an oxindole, thus forcing condensation only at the (8-position. That the j8-position of oxindoles is an adequate anionoid source is shown by the recent demonstration 

CCLXXIV, reminisoent of the strychnine progenitor above. The first step of this reaction must be formation of an anhydro salt CCLXXIIIa, the rapid condensation of which with the j8-position of the oxindole is in fact the previously invoked Mannich reaction Further support for this biogenetic variation is to be found in the existence of an intact j8-disub-stituted oxindole in gelsemine (353), an alkaloid which also appears to 

The ability of plants to utilize both the major biogenetic routes (to CCLXIX and CCLXX) is amply demonstrated by the various Stryehnos species, some of which elaborate the strychnine family of alkaloids, some of which (the South American Stryehnos) elaborate yohimbine types (curare alkaloids). Even more striking is the biosynthesis in the one plant Gdsemium sempervirens (not a Stryehnos) of both gelsemine 

More recently, a synthetic approach through the 2,3-benzpyrro-colines (CCLXXVI) took advantage of that system s propensity for C-alkylation to achieve the crucial quaternary center at the indolic 

Poulter has reviewed the evidence supporting an ionization-condensation-elimination mechanism (Vol. 8, p. 24) in the prenyl-transfer reaction. 

Yoshiie, T. Imamura, K. Hasegawa, M. Miyahara, S. Yamamura, and O. Ito, Bull. Chem. 

2714 for data on TiCU-MeOH photoreactions, see also Vol. 7, p. 33. 

Miyano, H. Watanabe, H. Ushiyama, Y. Yamada, and H. Hashimoto, Nippon Kagaku Kaishi, 

Synthesis, 1978,140 for pulegone bromination, the previously reported (Vol. 7, p. 8) enol 

the common precursor in the biosynthesis of heme and vitamin Bn, is synthesized from L-glutamate in archaebacteria, anaerobic bacteria and 

Removal of the CH2-group attached to C20 carbon and formation of a direct bridge between rings A and D. 

Methylations at C2, C7, C20, Cn, C12, Ci and C15 (Battersby, 1994). S-adenosylmethionine serves as donor of methyl groups. Methylations at C12 and Cn are accompanied by reduction of pyrrole rings C and D. Ligation of 5 -deoxyadenosine with cobalt. 

Divalent metal ions were found (Schneider et al., 1995) to be competitive inhibitors of the cobalt binding by propionibacterial cells. Among the metals studied, Ni, Mn and Mg were the strongest, while Pb and Ca the weakest inhibitors. KCl at concentrations above 0.2 M also significantly inhibited the binding of cobalt. In bacteria exposed to thermal shock at 60°C the cobalt-binding capacity increased several-fold. 

Recently, additional intermediates were isolated from P. shermanii (Scott et al, 1996, 1998) Co-precorrin-3 and a compound called factor-4, which represents a further modification of Co-precorrin-3. 

Rearranged labdane skeletons arise via a series of associated hydride and methyl shifts, usually involving concerted tra/ts-migrations of the participating substituents. 

Steps proposed for the biogenesis of rearranged ewMabdanes appear to correspond to the mechanisms indicated for the normal-labdanes, differing only in the opposite orientivity of the migrating groups. 

---

Farnesol pyrophosphate is an immediate precursor of squalene, the key intermediate in steroid and triterpenoid biogenesis, which arises from the coupling of two farnesol pyrophosphate molecules or of C,s units derived therefrom. The numerous types of sesquiter-penoid carbon skeletons represent various modes of cyclization of farnesol (sometimes with rearrangement) and it is probable that farnesol pyrophosphate is also the source of these compounds. 

G. O. AspiuaU, iu F. Loewus ed.. Biogenesis of Plant Cell Wall Polysaccharides, Academic Press, Inc., New York, 1973. 

P. Lewis and M. Paice, eds., Flant Cell Wall Polymers Biogenesis and Degradation, ACS Symposium Series, Washington, D.C., 1989, p. 299. 

R. M. Brown, Jr., ed.. Cellulose and OtherlAaturalPolymer Systems Biogenesis, Structure, and Degradation, Plenum Press, New York, 1982. 

The literature of alkaloids can conveniently be divided into five sections, dealing with (1) the occurrence and distribution of these substances in plants (2) biogenesis, or the methods by which alkaloids are produced in the course of plant metabolism (3) analysis, ranging from the commercial and industrial estimation of particular alkaloids to the separation, purification and description of the individual components of the natural mixture of alkaloids, which normally occurs in plants (4) determination of structure and (5) pharmacological action. 

Comparatively few alterations have been made since 1989 in the structures accepted for well-known alkaloids. A slight but important change has been adopted in the formula of strychnine and contributions to the chemistry of that alkaloid and its associates are still being made, though the formula seems now so well established that Woodward has recently suggested and discussed a scheme for the biogenesis of strychnine on which Robinson has commented favourably. Robinson has also proposed a scheme for the biogenesis of emetine. This involves a modification in the formula of that alkaloid, which is supported by Dewar s interpretation of the results of recent chemical work on emetine by Karrer et al., by Spath and by Pailer. ... 

A characteristic of all the above reactions is that the yield of the aldoliza-tion product depends on the pH of the reaction mixture (324), the maximum yield usually occurring near pH 7. Such reactions have been carried out in vitro in dilute aqueous buffer under so-called physiological conditions, i.e., conditions attainable in the living cell. Although this oversimplified technique for the study of alkaloid biogenesis is now being abandoned in favor of experiments in vivo with labeled precursors, such reactions are still of interest to organic chemists. 

Mitochondria Bioenergetics, Biogenesis and Membrane Structure, Packer, L., and Gomez-Pnyon, A., eds. New York Academic Press. 

These authors formulated the major steps in the biogenesis of the harmala bases as a condensation of a tryptamine derivative (460) with acetaldehyde to yield a l,2,3,4-tetrahydro-)3-carboline (461), which on oxidation in two stages would give harmaline (462 R = OCH3) and then harmine (463 R = OCH3). 

Conformational study of geissoschizine isomers and their model compounds (geissoschizine is the indolo[2,3-fl]quinolizidine derivative considered to be an important participant of indole alkaloids biogenesis) 99H(51)649. 

Biogenesis of manzamine alkaloids ((3-carboline marine alkaloids) 97H(46)765, 97YGK1114. 

Although this isoquinoline at first bears little structural resemblance to morphine (108), careful rearrangement of the structure (A) shows the narcotic to possess the benzylisoquinoline fragment within its framework. Indeed, research on the biogenesis of morphine has shown that the molecule is formed by oxidative coupling of a phenol closely related to papaverine. 

The enantiomeric distribution of the components of essential oils can provide information on the authenticity and quality of the oil, on the geographical origin and on their biogenesis (2). 

---