Mevalonate Pathways - Terpenes Steroids (1) PDF

STK31003 Terrestrial Natural Product Chemistry MEVALONATE PATHWAYS: TERPENES AND STEROIDS  TERPENES  Terpenes are a large and varied class of hydrocarbons, produced primarily by a wide variety of plants, particularly conifers.  They are the major components...

STK31003 Terrestrial Natural Product Chemistry MEVALONATE PATHWAYS: TERPENES AND STEROIDS  TERPENES  Terpenes are a large and varied class of hydrocarbons, produced primarily by a wide variety of plants, particularly conifers.  They are the major components of resin, and of turpentine produced from resin. The name "terpene" is derived from the word "turpentine".  Turpentine is obtained by distilling the gum from various species of pine. It is a mixture of isomeric terpene hydrocarbons Turpentine oil is applied to the skin for joint pain, muscle pain, nerve pain, and toothaches. People sometimes breathe in (inhale) the vapors of turpentine oil to reduce the chest congestion that goes along with some lung diseases. In foods and beverages, distilled turpentine oil is used as a flavoring  TERPENOIDS When terpenes are modified chemically, such as by oxidation or rearrangement of the carbon skeleton, the resulting compounds are generally referred to as terpenoids.  TERPENES AND STEROIDS  Terpenes and terpenoids are the primary constituents of the essential oils of many types of plants and flowers.  Essential oils are used widely as natural flavor additives for food, as fragrances in perfumery, in aromatherapy, and in traditional and alternative medicines.  Synthetic variations and derivatives of natural terpenes and terpenoids also greatly expand the variety of aromas used in perfumery and flavors used in food additives. Spearmint’s essential oil has cooling Rosemary essential oil can: effect on nerves and muscles also Improves Memory means that it’s used in topical treatments Improves Mood for muscular aches and pains, Reduces Depression headaches, and migraines. It also has Increases Alertness known antibacterial properties, not only Soothes Digestion harnessed for disinfectants, but also in Relieves Muscle Aches And Pain treating infection, promoting wound Anti-Itch healing, and tackling skincare issues. Natural Insecticide And as if that’s not enough, this mighty Anti-Inflammatory herb also has potent decongestant action Antioxidant which is why it can be found in cold Antiseptic preparations and sometimes used to Antibacterial treat asthma or respiratory issues. Anti-Fungal Essential Oil Composition Spearmint Essential oil composition Essential oils of Rosemary  TERPENES AND STEROIDS  Plant terpenoids are extensively used for their aromatic qualities. They play a role in traditional herbal remedies and are under investigation for antibacterial, antineoplastic and other pharmaceutical effects.  Terpenoids contribute to the scent of eucalyptus, the flavors of cinnamon, cloves and ginger. Well-known terpenoids include citral, menthol, camphor and the cannabinoids found in the Cannabis plant. Eucalyptus melliodora Cymbopogon Cinnamomum verum  ISOPRENOIDS  Present in all living organisms – but unusually diverse: (> 25,000 distinct plant isoprenoids identified!!), possibly the largest class of natural products.  Isoprene (2-methyl-1,3-butadiene) recognized as the basic constituent of “terpenes” by O. Wallach (Nobel prize in chemistry, 1910)  ISOPRENOIDS Ruzicka (N.P. in chemistry, 1939) formulated “biogenic isoprene rule” which hypothesized that there was such a universal isoprene precursor  ISOPRENOIDS  Bloch and Lynen (N.P. in medicine or physiology, 1964) established the basic elucidation of the biosynthetic pathway.  Their discoveries concerned the mechanism and regulation of the metabolism of cholesterol and fatty acids, which relate to the understanding of steroid and fat metabolism.  Bloch showed that acetyl CoA is the precursor for steroid biosynthesis; and Lynen identified the “active isoprene” (isopentenyl pyrophosphate), as the precursor to all isoprenoids, which confirmed Ruzicka’s speculation 25 years earlier. Isopentenyl pyrophosphate Dimethylallyl pyrophosphate TERPENOIDS AND STEROIDS  Terpenes are derived biosynthetically from units of isoprene, which has the molecular formula C5H8.  The basic molecular formulas of terpenes are multiples of that, (C5H8)n where n is the number of linked isoprene units.  This is called the isoprene rule or the C5 rule. The isoprene units may be linked together "head to tail" to form linear chains or they may be arranged to form rings. One can consider the isoprene unit as one of nature's preferred building blocks. TERPENOIDS AND STEROIDS  Acetyl CoA is the precursor leading to isopentenyl pyrophosphate (IPP)  Isopentenylpyrophosphate (IPP) is the universal precursor for all isoprenoid synthesis  Non-mevalonate Pathway 1-Deoxy-D-xylulose 5-phosphate (DOXP; DXP) 2-C-methylerythritol 4-phosphate (MEP)  is 30 10 28 40 Acctil-Col 2 GAP  IPP BIOSYNTHESIS  Initial steps of the pathway: three molecules of acetyl-CoA are fused to produce the six-carbon (C6) 3-hydroxy-3- methylglutaryl-CoA (HMG-CoA).  The first two reactions are catalyzed by acetyl-CoA acetyltransferase and HMG-CoA synthase. From here, HMG-CoA, is reduced in two steps, each requiring NADPH. This step, catalyzed by HMG-CoA reductase (HMGR), is extremely important in animal systems, in that it is the rate- limiting reaction in cholesterol biosynthesis.  Mevalonate formed from the reduction of HMG-CoA is sequentially phosphorylated by two distinct soluble enzymes, mevalonate kinase and 5-phosphomevalonate kinase. The 5-pyrophosphomevalonate formed is then converted to IPP by a concerted decarboxylative elimination by pyrophosphomevalonate decarboxylase, requiring ATP and a divalent metal ion  Biosynthesis GPP derivatives - monoterpene FPP derivatives - sesquiterpenes; leading to sterols and steroids GGPP (GGDP) derivatives - plant growth regulators; defense substances; leading to carotenoids.  9 10H CLASSIFICATION  y Hemiterpenes consist of a single isoprene unit. Isoprene itself is considered the only hemiterpene, but oxygen-containing derivatives such as prenol and isovaleric acid are hemiterpenoids. Mou  Monoterpenes consist of two isoprene units and have the molecular formula C10H16. Examples of monoterpenes are: geraniol and limonene.  Sesquiterpenes consist of three isoprene units and have the molecular formula C15H24. Examples of sesquiterpenes are: farnesol. The sesqui- prefix means one and a half.  CLASSIFICATION  Diterpenes are composed for four isoprene units and have the molecular formula C20H32. They derive from geranylgeranyl pyrophosphate. Examples of diterpenes are cafestol, kahweol, cembrene and taxadiene (precursor of taxol). Diterpenes also form the basis for biologically important compounds such as retinol, retinal, and phytol.  Sesterterpenes, terpenes having 25 carbons and five isoprene units, are rare relative to the other sizes. The sester- prefix means half to three, i.e. two and a half. Some examples includes astellatol, nitidasin, variecolin and aleurodiscal.  CLASSIFICATION  Triterpenes consist of six isoprene units and have the molecular formula C30H48. The linear triterpene squalene, the major constituent of shark liver oil, is derived from the reductive coupling of two molecules of farnesyl pyrophosphate.  Squalene is then processed biosynthetically to generate either lanosterol or cycloartenol, the structural precursors to all the steroids.  CLASSIFICATION  Tetraterpenes contain eight isoprene units and 64 have the molecular formula C40H56 -. Biologically important tetraterpenes include the acyclic lycopene, the monocyclic gamma-carotene, and the bicyclic alpha- and beta-carotenes.  Polyterpenes consist of long chains of many isoprene units. Natural rubber consists of polyisoprene in which the double bonds are cis. Some plants produce a polyisoprene with trans double bonds, known as gutta-percha.  Monoterpene Monoterpenes are a class of terpenes that consist of two isoprene units and have the molecular formula C10H16. Monoterpenes may be linear (acyclic) or contain rings. Biochemical modifications such as oxidation or rearrangement produce the related monoterpenoids.  Monoterpene  Biosynthetically, isopentenyl pyrophosphate and dimethylallyl pyrophosphate are combined to form geranyl pyrophosphate.  Monoterpene  Elimination of the pyrophosphate group leads to the formation of acyclic monoterpenes such as ocimene and the myrcenes.  Hydrolysis of the phosphate groups leads to the prototypical acyclic monoterpenoid geraniol.  Additional rearrangements and oxidations provide compounds such as citral, citronellal, citronellol, linalool, and many others.  Many monoterpenes found in marine organisms are halogenated, such as halomon.  Linalool Myrcene Citral Citronellal Ocimene Halomon Geraniol  Monocyclic In addition to linear attachments, the isoprene units can make connections to form rings. The most common ring size in monoterpenes is a six-membered ring. A classic example is the cyclization of geranyl pyrophosphate to form limonene. t Me  Cyclic Monoterpenoid  Cyclicmonoterpenes include the characteristic and principal constituents of peppermint (Mentha piperita) and spearmint (M. spicata) essential oils. Limonene is an intermediate in the formation of these mint aroma compounds Spearmint Essential oil Composition  Cyclic Monoterpene Numerous other modified cyclic isoprenoids are found in plants and many have important properties in pest resistance or control, medicine, etc.  Bicyclic  Geranyl pyrophosphate can also undergo two sequential cyclization reactions to form bicyclic monoterpenes, such as pinene which is the primary constituent of pine resin  Other bicyclic monoterpenes include carene, sabinene, camphene, and thujene. Camphor, borneol and eucalyptol are examples of bicyclic monoterpenoids containing ketone, alcohol, and ether functional groups, respectively.  Sesquiterpenes  Sesquiterpenes are a class of terpenes that consist of three isoprene units and have the molecular formula C15H24. Like monoterpenes, sesquiterpenes may be acyclic or contain rings, including many unique combinations. Biochemical modifications such as oxidation or rearrangement produce the related sesquiterpenoids. *  Sesquiterpene  Different sesquiterpene cyclases can utilize the same substrate to produce very different reaction products. The reaction mechanism is similar to GPP cyclases in which the generation of an electron deficient carbon atom is due to the loss of the diphosphate substituent, a very strong electron- withdrawing group. The resulting carbocation then attacks another carbon atom that is electon-rich by virtue of its association with a double bound  Sesquiterpenes  Biosynthetically, when geranyl pyrophosphate reacts with isopentenyl pyrophosphate, the result is the 15- carbon farnesyl pyrophosphate which is an intermediate in the biosynthesis of sesquiterpenes such as farnesene. Oxidation can then provide sesquiterpenoids such as farnesol. Acyclic Farnesol Farnesene  Monocyclic  With the increased chain length and additional double bond, the number of possible ways that cyclization can occur is also increased and there exist a wide variety of cyclic sesquiterpenes. In addition to common six-membered ring systems such as is found in zingiberene, a consitituent of the oil from ginger, cyclization of one end of the chain to the other end can lead to macrocyclic rings such as humulene. Monocyclic Zingeberine Humulene  Bicyclic  In addition to common six-membered rings such as in the cadinenes, one classic bicyclic sesquiterpene is caryophyllene, from the oil of cloves, which has a nine- membered ring and cyclobutane ring. Additional unsaturation provides aromatic bicyclic sesquiterpenoids such as vetivazulene and guaiazulene.  Bicyclic Sesquiterpene Vetivazulene Caryophyllene Cadinene Guaiazulene  Tricylic  With the addition of a third ring, the possible structures become increasingly varied. Examples include longifolene, copaene and the alcohol patchoulol. Longifolene Copaene Patchoulol  Diterpenoid  Diterpene is a C20 compounds  Widely found in plant resins  Various molecular skleton either as linear such as phytol; monocyclic compounds such as vitamin A; bicyclic such as sclareol and manool; tricyclic such as sugiole; tetracyclic such as gibberellin; macrocyclic such as toxinin and others  Diterpenoids  The diterpenoids are widespread in the plant kingdom, and they often are encountered in the resins of conifers, woody Leguminosae (legumes) examples pea and beans, Compositae (composites) examples lettuce and sunflower, and members of the Euphorbiaceae examples cassava and rubber tree.  More than 3,000 different diterpenoid structures have been defined, all of which appear to be derived from GGDP.  Diterpenoids  The most common diterpene is phytol, the acyclic alcohol side chain of chlorophyll.  Most diterpenoids are cyclic. The macrocyclic diterpenes, such as casbene, cembrene, and taxadiene, are formed by cyclizations analogous to those of the monoterpene and sesquiterpene series. Casbene Cembrene Carbocation Casbene  Abeatic acid Levopyramic acid Agatic acid Feruginole Phytol Vitamin A Sclareol Manool  Triterpenoid  Triterpenoids are widely distributed  The simplest triterpenoid in the acyclic form known as squalene.  Squalene is the precursor to all other triterpenoids and steroids  Triterpenoids exist in various functional groups such as alcohol, carboxylic acids, aldehydes etc.  Tetracyclic Triterpenoid Lanosterol Agnosterol  Pentacyclic Triterpenoids - amyrin - amyrin Ursolic acid Asiatic acid -amyrin -amyrin Oleanolic acid  Lupeol Lupeol Betuline Lupeol was shown to have various pharmacological properties, inducing anti-inflammatory and anti- arthritic responses and inhibition of tumor growth  STEROIDS  Derived from squalene (C30)  Steroids C18-C29  All steroids are based on cyclopentanoperhydrophenanthrene systems  Steroids 5- series and 5- series Cyclopentanoperhydrophenanthrene Steroid 5- series Steroid 5- series  Steroids Hormones are the true long-range chemical messengers, secreted by the ductless glands into the interstitial spaces, taken up into the blood stream through fenestrated capillaries, and targeting far distant cells.  Steroids Steroids form an important group of compounds based on the fundamental saturated tetracyclic hydrocarbon: 1,2-cyclopentanoperhydrophenanthrene (sterane or gonane).  The steroid hormones are all derived from cholesterol. Moreover, with the exception of vitamin D, they all contain the same cyclopentanophenanthrene ring and atomic numbering system as cholesterol.  The conversion of C27 cholesterol to the 18-, 19-, and 21-carbon steroid hormones (designated by the nomenclature C with a subscript number indicating the number of carbon atoms, e.g. C19 for androstanes) involves the rate-limiting, irreversible cleavage of a 6-carbon residue from cholesterol, producing pregnenolone (C21) plus isocaproaldehyde.  Common names of the steroid hormones are widely recognized, but systematic nomenclature is gaining acceptance and familiarity with both nomenclatures is increasingly important.  Steroids with 21 carbon atoms are known systematically as pregnanes, whereas those containing 19 and 18 carbon atoms are known as androstanes and estranes, respectively.  Pregnenolone: produced directly from cholesterol, the precusor molecule for all C18, C19 and C21 steroids Pregnenolone y = 0 1 - FIT V 40  STEROIDS  This nucleus, partially or completely hydrogenated, is generally substituted by methyl groups at C10 and C13. A chemical group (ketone, hydroxyl...) or an alkyl side-chain may also be present at C17.  Steroids may possess a nucleus derived from sterane by one or more C-C bond scissions or ring expansions or contractions.  STEROIDS  According to their chemical structure, the wide array of steroid molecules may be divided into several groups :  Sterols Brassinosteroids Bufadienolides Cardenolides Cucurbitacins Ecdysteroids Sapogenins Steroid alkaloids Withasteroids Bile acids Hormonal steroids  Cardiac Glycosides  Steroid with strong effect on cardiac system  Steroids attached to sugar moiety (at C-3)  Two important groups – Cardenolides C23 types steroids with 5 membered unsaturated lactone and bufadienolides C24 types steroids with 6 membered unsaturated lactone  Bufadienolides  They are typically polyhydroxy C24 steroids with a pentadienolide ring at C-17. The structure of hellebrigenin is given below as a typical example of bufadienolides.  Bufadienolides  They have been isolated from plants but mostly from animals. More than 250 compounds have been identified.  In plants, they are mostly glycosides with one to three sugars in a chain linked to the 3-hydroxyl group.  They are important for their cardiotonic activity. Furthermore, they possess insecticidal and antimicrobial properties, those produced by the toad skin are strongly poisonous.  Cardenolides  Their structure is closely related to bufadienolides but these C23 steroids possess a butenolide ring located at C-17. The structure of digitoxigenin is given below as a typical example of cardenolides.  Cardenolides  They are widely distributed in plants mainly as glycosides and are either toxic or insect deterrents.  As potent cardiotonics, these steroids were largely studied (digoxin and its derivative ouabain).  Monarch butterfly is well known to be highly toxic to birds because of cardenolides which come from the milkweed leaves eaten by its caterpillar. Monarch butterfly  Nerium oleander Thevetia peruviana Thevetia peruviana  Saponin  Classified as steroids saponin or triterpenoids saponins  Give thick foam  Hemolyze red blood cells  Kill small animals such as fish  Glycosidic bonds at C-3 with various sugars  Can be hydrolyze to give sugar and sugar free component (aglycon) known as sapogenin  Derris elliptica (tuba root) Derris elliptica is a wild plant or weed in agricultural fields which is traditionally used for poisoning fish and plant pests Foam Test For Quinoa (Chenopodium quinoa) Saponin BJ: erect habit, height between 1.20 and 2.10 m. Green panicle, branched, white grain, sweet taste TK: height between 1.60 and 2.30 m, branched, slightly compact, purple to orange purple at the beginning of maturity, white and large grains, diameter greater than 2 mm NC: branched up to the lower-third; height between 1.08-1.67 m. Vegetative cycle of 70 days. Green panicle at flowering and green-yellow at maturity, branched. Black seeds, 1.66 - 1.79 mm in diameter AM: slightly branched, erect, 1.80 m. high, large grain with orange color (2.5 mm.), vegetative cycle of 180 to 210 days (late), high content of saponins. DO: large grain with yellowish color, high content of saponins  Sapogenins They form the aglycon part of saponins which have well known detergent properties. They are oxygenated C27 steroids with an hydroxyl group in C-3. Common example is diosgenin.  Sapogenins  These steroids can mimic or regulate steroid hormones.  Thus, diosgenin can be chemically converted into corticosteroids, estrogens and progesterone.  They are extremely distributed in plants since they occur in over 90 plant families. They are used in nutrition, as herbal medicine, and in cosmetics.  Bile acids  The end products of cholesterol utilization are the bile acids, synthesized in the liver.  In mammals, the most common bile acids are C24 steroids with a carboxyl group at C-24 and up to three hydroxyl groups on the steroid nucleus, one being at C-3.  The most abundant bile acids in human bile are chenodeoxycholic acid (45%) and cholic acid (31%). These are referred to as the primary bile acids.  Bile Acids Synthesis and Utilization  The end products of cholesterol utilization are the bile acids, synthesized in the liver.  Bile acids are carried from the liver to the gallbladder, where they are stored for future use.  Synthesis of bile acids is one of the predominant mechanisms for the excretion of excess cholesterol.  However, the excretion of cholesterol in the form of bile acids is insufficient to compensate for an excess dietary intake of cholesterol. 1. Esophagus 2. Thoracic diaphragm 3. Stomach 4. Liver 5. Gallbladder 6. Duodenum 7. Pancreas 8. Spleen  Bile Acids  Within the intestines the primary bile acids (chenodeoxycholic acid and cholic acid ) are acted upon by bacteria and converted to the secondary bile acids, identified as deoxycholate (from cholate) and lithocholate (from chenodeoxycholate).  Both primary and secondary bile acids are reabsorbed by the intestines and delivered back to the liver via the portal circulation.  Bile Acids Synthesis of the 2 primary bile acids, cholic acid and chenodeoxycholic acid -The reaction catalyzed by the 7-hydroxylase is the rate limiting step in bile acid synthesis. Conversion of 7-hydroxycholesterol to the bile acids requires several steps. Only the relevant co-factors needed for the synthesis steps are shown the At live  Bile acids  Normally Side chain 5C with carboxylic acid  Bile acid types C24 such as cholic acid found in mammals  Bile acid type C27-28 found in reptiles and amphibian such as 3, 7, 12- trihydroxycaprostanic acids  Trihydroxycoprostanic acid (3α,7α,12α-trihydroxy-5β- Cholanic acid cholestan-26-oic acid) Cholic acid Deoxycholic Acid  Bile acids  Bile acids are reabsorbed by the intestines and delivered back to the liver via the portal circulation.  Within the liver the carboxyl group of primary and secondary bile acids is conjugated via an amide bond to either glycine or taurine before their secretion into the bile.  Bile acids  These conjugation reactions yield glycoconjugates and tauroconjugates, respectively.  They are hydrolized in the intestine.  The ultimate fate of bile acids is secretion into the intestine, where they aid in the emulsification of dietary lipids.  Bile acids  Conjugates of fatty acid with bile acids are a new class of molecules synthesized with the aim of reducing cholesterol crystallization in bile.  Among them, arachidyl amido cholic acid (Aramchol) was shown to be the most active to retard that process and may be of potential use in cholesterol gall stone disease in humans Aramchol -Arachidyl amido cholic acid  Clinical Significance of Bile Acid Synthesis  Their synthesis and subsequent excretion in the feces represent the only significant mechanism for the elimination of excess cholesterol.  Bile acids and phospholipids solubilize cholesterol in the bile, thereby preventing the precipitation of cholesterol in the gallbladder.  They facilitate the digestion of dietary triacylglycerols by acting as emulsifying agents that render fats accessible to pancreatic lipases.  They facilitate the intestinal of fat-soluble vitamins.