Medical Chemistry Lecture 12 2007 (J.S.) Eicosanoids Isoprenoids Terpenes and steroids Lipids II
Eicosanoids are a family of polyunsaturated C 20 fatty acid derivatives, (Greek eikosi – “twenty”), which act as local hormones and have a wide range of biological functions. All are derived from essential polyunsaturated fatty acids – arachidonic acid ( eicosatetraenoic, abbr. ETE) 20:4 ( 5,8,11,14 ) from the n -6 series, and – eicosapentaenoic acid (abbr. EPE) 20:5 ( 5,8,11,14,17 ) from the n -3 series. COO –
There are two major types of eicosanoids : – cyclic prostanoids , which can be held as derivatives of an unnatural 20-carbon fatty acid containing a 5-carbon (cyclopentane) ring called prostanoic acid: prostaglandins , prostacyclins , and related thromboxanes ; – acyclic leukotrienes and lipoxins C OO –
Cyclic eicosanoids - prostanoids: Prostaglandins Although prostaglandins are synthesized in nearly all cell types , the name denotes the tissue from which they were isolated for the first time (the prostate gland).. The major classes differing in the structure of the ring (as well as in its desaturation) are designated by letters (PGH, PGE, PGF, PGA, PGB), the numerical subscript denotes the number of carbon-carbon double bonds outside the ring of all eicosanoids, i.e. of both prostanoids and leukotrienes. Prostanoids with the subscript 2 (two double bonds in the side chains) are members of the second (or diene ) series that is synthesized from arachidonate 20:4 ( n -6), the other two double bonds of the precursor are lost in forming a ring. Those with the subscript 3 - the third (or triene ) series are synthesized from eicosapentaenoic acid 20:5 ( n -3).
Inactivated " secondary " prostaglandins PG A and PG B are produced by dehydration ( A – dehydration catalysed by an acid, B – dehydration catalysed by a base) PGE PGF PG H (an endoperoxide) in the intermediate in biosynthesis of all prostanoids. The most significant " primary " prostaglandins are PG E and PG F exhibiting very high biological activity. ( E – ether extractable, less polar than F – extractable into phosphate buffer) PGA PGB PGH
Prostaglandin E 2 PGE 2 Prostaglandin F 2 α PGF 2 α
(abbreviation PGI) are the derivatives of PGH, in which C-6 of the short side chain closes the five-membered heterocycle fused with the cyclopentane ring: Prostacyclins Prostacyclin PGI 2 6
Thromboxanes originate through transformation of the common precursor of all prostanoids – endoperoxide PGH. Instead of cyclopentane ring, those compounds contain a six-membered heterocycle oxane . The name denotes that they are specific products of thrombocytes (blood platelets). Thromboxane TXA 2
Acyclic eicosanoids: Leukotrienes The characteristic feature of these acyclic 20-carbon compounds produced primarily in leuko cytes and mast cells is the presence of three conjugated double bonds ( trienes ), the position of which may be different and the configuration either trans or cis. The classes are designated by letters (LTA, LTB – LTE), the subscript denotes the total number of double bonds. COO – O LTA 4 LTB 4
Peptidoleukotrienes (leukotrienes class C, D, E) – carbon atom 6 binds the sulfur atom of glutathione ( -Glu Cys Gly) in the class LTC , of cysteinyl-glycine in the class LTD , and of only cysteine in the class LTE . Leukotrienes are the most effective eicosanoids, e.g. their vasodilating effect is about 5 000 times more intensive than that of the same amount of histamine. OH S Cys Gly LTD 4 Slow-reacting substance of anaphylaxis (SRS-A)
are hydroxylated derivatives of arachidonic acid (ETE) and eicosapentaenoic acid (EPE) produced by combined effect of lipoxygenases catalysing hydroxylation of carbons 5, 12, or 15. The term lipoxin is derived from " lipoxygenase interaction products“. Lipoxins LXA 4 5-Hydroxytetraenoic acid (5-HETE)
Eicosanoids bronchoconstriction, vasodilatations various cell types lipoxin LXA 4 bronchoconstriction, vasoconstriction leukocytes, mast cells leukotriene LTD 4 platelet aggregation, vasoconstriction blood platelets thromboxane TXA 2 vasodilatation, inhibition of platelet aggregation endothelial cells, smooth muscle cells of blood vessels prostacyclin PGI 2 vasoconstriction nearly all cell types prostaglandin F PGF 2α inflammatory reaction, vasodilatation nearly all cell types prostaglandin E PGE 2 The most remarkable effect: Synthesized in Structural group Examples
Isoprenoids are a family of natural products whose structures are composed of five-carbon isoprene units . The unit consists of a four-carbon chain with a one-carbon branch at carbon 2. Isoprene unit C 5 regular tail-to-head attachment (the head is usually directed to the free end of a molecule, the tail to the inner part) irregular attachment tail-to-tail (tail-to-tail and head-to-head linkages are less frequent) "head" " tail"
Isoprene 2-methylbuta-1,3-diene Isoprene unit of polymers Terpenes are isoprenoids mainly of plant origin that can be isolated from essential oils of plants. Some terpenes play also an important role in metabolism of animals. Numerous terpenes contain various functional group (mostly alcoholic or phenolic hydroxyl, carbonyl), may be saturated or unsaturated, acyclic or cyclic.
According to the number of isoprene units comprising the molecules, terpenes are classified as monoterpenes with two isoprene units, C 10 , sesquiterpenes C 15 – three isoprene units, diterpenes C 20 – four isoprene units, triterpenes C 30 – six units, tetraterpenes C 40 – eight units, and polyterpenes , which comprise more isoprene units.
Isopentenyl diphosphate Dimethylallyl diphosphate All isoprenoids are synthesized from acetyl-CoA by way of an important intermediate isopentenyl diphosphate and its isomer dimethylallyl diphosphate . Dimethylallyl diphosphate and isopentenyl diphosphate are basal units for polymerization. They join together to give a monoterpene geranyl diphosphate : A sesquiterpene farnesyl diphosphate originates by joining the third basal unit:
occurs in oil of geranium but also constitutes about 50 % of rose oil extracted from rose petals. Geraniol Examples of monoterpenes ( C 10 ) with open chain Citral (aldehyde) Volatile monoterpenes provide plants and flowers with much of their fragrance. Some of them are constituents of perfumes and flavours.
Menthol (peppermint oil) Thymol - Pinene (turpintine) 2- Bornanone (camphora) Examples of cyclic monoterpenes ( C 10 ) that may be taken as derivatives of menthane , a hydrocarbon:
Phytol is a diterpene ( C 20 ) alcohol, three of its four isoprene units are fully hydrogenated (saturated): Phytyl occurs as a side-chain attached to 1,4-naphtoquinone in phylloquinone (vitamin K 1 ): Squalene is a triterpene ( C 30 ) , a symmetrical hydrocarbon - the intermediate in the biosynthesis of cholesterol and other steroids: extended conformation folded conformer
Carotenoids are tetraterpenes ( C 40 ) – natural pigments, present in leaves of all green plants. Unlike other terpenes their molecules comprise an extensive system of conjugated double bonds . -Ionone – a natural ketone (C 13 ) is a cause of a fragrant scent of the violet. -ionone ring Oxidative splitting in the middle of -carotene molecule produces retinol (vitamin A). Other types of carotenes differ from -carotene in different structures of their ends. Oxygenous derivatives of carotenes are named xanthophylls . β-Carotene is the most important carotene that contains two β-ionone rings at both ends of the molecule (this hydrocarbon is symmetrical). Lycopene is a red aliphatic hydrocarbon (without any ring), e.g., in tomato and red pepper.
Retinol ( vitamin A ) originates by oxidative splitting of carotenes which contain a -ionone ring. In the body, retinol gives retinal by reversible oxidation, or it is oxidized irreversibly to retinoate ( retinoic acid ). all- trans -retinal 1 1 11- cis -retinal Retinal is the photosensitive component of visual purple – rhodopsin . After absorption of photon (s) , all- trans -retinal undergoes isomerization to 11- cis- retinal, which initiates the cascade of reactions that result in visual percept.
In the biosynthesis of plasma type glycoproteins, dolichol diphosphate is anchored in the membrane of endoplasmic reticulum and glycosyls are added stepwise to its diphosphate group. After the oligosaccharide is built up, it is transferred to the protein and linked through N -glycosidic bond to the side chain of asparaginyl residue). Dolichol is a long-chain polyprenol that contains about 20 isoprene units (about 100 carbon atoms). Double bonds in cis -configuration, the last isoprene unit (α-unit) is saturated. Dolichol diphosphate ( Dol-P-P ) n = 10 n H Ubiquinone (coenzyme Q)
Steroids The biological precursor of steroids is a 30-carbon linear branched hydrocarbon (triterpene) squalene . From squalene, steroidal alcohols are synthesized through a complex process that, in its final stages, involves the loss of several carbon atoms. The typical steroidal alcohol in animals is cholesterol , from which all other steroids of biological importance originate. Cholesterol has 27 carbon atoms, most of its derivatives even less. Steroids are therefore not strictly terpenes, but they are related to terpenes in the sense that they are biosynthesized by a similar route.
Cyclopentanoperhydrophenanthrene (also the name sterane is used) Phenanthrene (fused aromatic benzene rings) Perhydro phenanthrene (fused cyclohexane rings) There are eight stereoisomers of sterane which differ in cis and trans configurations of A/B, B/C, and C/D ring fusions.
The rings in steroids are denoted by the letters A, B, C, and D: Carbon atoms in steroids are numbered in a specific manner: 1 10 2 3 4 5 9 6 7 8 11 15 14 16 17 13 12 A B C D Carbons outside the rings: 17 22 23 27 26 25 21 20 19 18 24
The two fused cyclohexane rings in chair conformations: trans fusion cis fusion A trans fusion yields a nearly planar structure, whereas a cis fusion gives a buckled structure.
5 - Gonane From the eight stereoisomers of sterane, two are named gonanes : The fusion of the steroid rings B ands C as well as C and D is trans, the fusion of the rings A and B is either trans (so called 5 α-) or cis (5β-configuration). In nearly all natural steroids the atoms attached to C-10, C-8, C-13 lie above the plane containing the four rings – they are β oriented. The atoms (substituents) that are below the plane are α oriented.
5 - Gonane The cis fusion of the rings A and B (characteristic for the bile acids, with the buckled structure of the steroid skeleton) occurs rarely.
Substituents: C 17 Gonane (none) C 18 Estrane 13-methyl C 19 Androstane 10,13-dimethyl C 21 Pregnane 10,13-dimethyl- 17 β -ethyl C 24 Cholane 10,13-dimethyl-17 β- (2-pentyl) C 27 Cholestane 10,13-dimethyl-17 β -[2-(6-methyl)heptyl] (C 28 Ergostane C 29 Stigmastane) The nomenclature of steroid hydrocarbons
5 α - Estrane C 18 Estra-1,3,5(10)-triene (ring A is aromatic ) 13 β-methyl-5α-gonane C-18
10,13-Dimethyl-5 α-gonane 5 α - Androstane C 19 C-19
17 β-Ethyl-5α-androstane 5 α - Pregnane C 21
17 β-(2-pentyl)-5β-androstane 5 β - Cholane C 24 Five -carbon side chain at C-17 C-24
5 α - Cholestane C 27 Eight -carbon branched side chain at C-17
Ergostane C 28 The 3 β-hydroxyderivative is a phytosterol from which in plants ercalciol (ergocalciferol, vitamin D 2 ) is synthesized. Stigmastane C 29 CH 3 CH 2
C 27 C 24 C 21 C 19 C 18 Cholesterol is the precursor for other important steroids:
Cholesterol Cholest-5-ene-3 β-ol C 27
Calciol (cholecalciferol, vitamin D 3 ) is synthesized from 7-dehydrocholesterol by photolysis that is a cause of opening of the ring B:
Bile acids are various hydroxy derivatives of 5 β-cholan-24-oic acid C 24 Cholic acid 3 α,7α,12α-Trihydroxy-5β-cholan-24-oic acid Example:
Progesterone is a progestin ( gestagen ) : it prepares the lining of the uterus for implantation of an ovum and is also essential for the maintenance of pregnancy. C 21
Corticoids are hormones produced in the adrenal cortex. Glucocorticoids (such as cortisol ) promote gluconeogenesis and the formation of glycogen, enhance the degradation of proteins and fat, and inhibit the inflammatory response. They enable animals to respond to stress. Mineralocorticoids (primarily aldosterone ) act on the kidney to increase the reabsorption of Na + and the excretion of K + , which leads to an increase in blood volume and blood pressure. C 21
Cortisol, the major glucocorticoid, is synthesized from progesterone by hydroxylations at C-17, C-21, and C-11. Cortisol (hydrocortisone) 11 β,17α,21-Trihydroxypregn-4-ene-3,20-dione Glucocorticoid
Testosterone 17 β-Hydroxyandrost-4-ene-3-one C 19 Androgens are responsible for the development of male secondary sex characteristics.
Estradiol Estra-1,3,5(10)-triene-3,17 β-diol C 18 Estrogens are required for the development of female secondary sex characteristics and, along with progesterone, also participate in the ovarian cycle .