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102 4. Biosynthesis of Natural Products Derived from Shikimic Acid

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102 4. Biosynthesis of Natural Products Derived from Shikimic Acid 102 4. Biosynthesis of Natural Products Derived from Shikimic Acid 4.1. Phenyl-Propanoid Natural Products (C6-C3) The biosynthesis of the aromatic amino acids occurs through the shikimic acid pathway, which is found in plants and microorganisms (but not in animals). We (humans) require these amino acids in our diet, since we are unable to produce them. For this reason, molecules that can inhibit enzymes on the shikimate pathway are potentially useful as antibiotics or herbicides, since they should not be toxic for humans. COO COO NH R = H Phenylalanine 3 R = OH Tyrosine R NH3 N Tryptophan H The aromatic amino acids also serve as starting materials for the biosynthesis of many interesting natural products. Here we will focus on the so-called phenyl-propanoide (C6-C3) natural products, e.g.: OH OH OH HO O HO OH HO O Chalcone OH O a Flavone OH O OH O a Flavonone OH OH Ar RO O O O HO O O OH O OR OH Anthocyanine OH O a Flavonol Podophyllotoxin MeO OMe OMe OH COOH Cinnamyl alcohol HO O O Cinnamic acid OH (Zimtsäure) Umbellierfone OH a Coumarin) MeO OH O COOH HO Polymerization OH Wood OH HO OH O OH MeO OMe Shikimic acid O HO 4.2. Shikimic acid biosynthesis The shikimic acid pathway starts in carbohydrate metabolism. Given the great social and industrial significance of this pathway, the enzymes have been intensively investigated. Here we will focus on the mechanisms of action of several key enzymes in the pathway. The following Scheme shows the pathway to shikimic acid: 103 COO- COO- Phosphoenolpyruvate HO COO- 2- O O3P-O 2- O3P-O DHQ-Synthase 2- O3P-O DAHP-Synthase HO OH O OH O HO OH OH OH 3-Deoxy-D-arabinoheptulo- Dehydroquinate sonate-7-phosphate (DAHP) (DHQ) D-Erythrose-4-phosphate COO- COO- COO- Shikimate Shikimate Dehydroquinase Dehydrogenase Kinase O OH 2- OH HO OH O3P-O OH OH OH Dehydroshikimate Shikimate Shikimate-3-phosphate COO- COO- - 2-O P-O COO- COO OH 3 Chorismate Synthase O COO- EPSP-Synthase Isochorismate 2-O P-O O COO- O COO- 3 Vitamin K OH OH 5-Enolpyruvylshikimate- O Chorismate 3-phosphate (EPSP) HOOC Anthranilate Chorismate COOH Synthase Mutase COO- COO- ⊕ ⊕ NH OH NH3 3 Aminodeoxychorismate Tryptophan Synthase Prephenic acid O COO- Anthranilic acid - COO- COO COO- COO- THF NH HO 3 NH3 O COO- ⊕ ⊕ p-Aminobenzoic acid Tyrosine ⊕ ⊕NH3 NH3 Phenylalanine DAHP-Synthase At first sight this seems to be a straightforward Aldol-like reaction between phosphoenolpyruvate (PEP) und erythrose-4-phosphate. However, for unknown reasons, Nature has made this more complicated than it appears: - - O COO O - P DAHP-Synthase COO - O O O 2-O P-O 2-O P-O 3 3 O HO HO OH OH OH Experiments with 18O-labelled PEP have shown that all of the 18O label is lost with phosphate - none is incorportated into the aldol-product. Other labelling experiments with Z-[3-3H]-PEP have shown that the reaction proceeds stereospecifically, even with respect to the new prochiral center in the product. The Si- face of the PEP must add to the Re-face der carbonyl group. A likely mechanism is : 104 - O - O COO O COO- O O - P -O COO O P - O O O HB - HB 2- O O3P-O HA HA 2- 2-O P-O H O3P-O 3 HO OH O OH HO H HO H OH OH OH 3-Dehydroquinate Synthase This is a very interesting enzymic reaction. At first sight, it is not clear what the reaction mechanism is. The enzyme needs NAD+ as coenzyme, but this is not consumed during the reaction (no net redox change): 1 COO- HO COO- 2 O DHQ-Synthase 2- O3P-O 6 4 + 5 NAD HO OH O OH OH OH 3-Deoxy-D-arabinoheptulo- Dehydroquinate (DHQ) sonate-7-phosphate (DAHP) It was shown that when DAHP is labelled at C5 or C6 with 2H (deuterium), then a significant kinetic isotope effect on the reaction rate can be observed (i.e. slower with the deuterated substrates). This implies that both the C(6)-H and the C(5)-H bonds are cleaved during the reaction. The following mechanism was suggested: H O HO HO H O HOOC O HOOC O O-P O OH H OH - P O + NADH O H NAD O- HO O OH HO HOOC O HOOC O O H OH H H HO HO H OH O - DHQ HOOC O HOOC O O OH This mechanism has been suggested, on the basis of studies carried out over many years. At first sight the enzyme appears to catalyze: 1) a redox reaction, 2) an elimination, 3) another redox reaction, 4) an aldol- like reaction. At least the chemical logic of oxidizing the alcohol group then becomes clear. How does one active site achieve all this ?? 105 Modifications to the phosphate at C-7 have a dramatic effect on rate, suggesting that it plays an active role in the elimination step. It is known that the labelled substrates 7S- und 7R-[7-3H]-DAHP are converted into labelled products with overall inversion of configuration at C7. So the C-C bond-forming step also proceeds stereospecifically (Proc. Natl. Acad. Sci.USA 1970, 67, 1669). In a model study, however, it was also shown that the the aldol-like reaction can proceed rapidly and also stereospecifically without catalysis by the enzyme (JACS, 1988, 110, 1628): H H H HO HO o HO H OH hν, 0 C OH OH HOOC O HOOC O HOOC H H O O OH OH D O D D NO2 Apparently, the steps that really need the catalytic action of the enzyme, in order to achieve rapid turnover, are those involving the redox changes (alcohol ketone) with the coenzyme NAD. The catalytic power of the enzyme appears to be focused on making these steps fast, and perhaps is less crucial for providing catalysis for the elimination and aldol-like reactions, which proceed fast anyway if the substrate is bound in an optimal conformation. EPSP-Synthase The sixth step in shikimic acid biosynthesis is the EPSP-synthase reaction. This enzyme has been intensively investigated, not least because it is the target of the commercially important herbicide Glyphosate, which inhibits the enzyme : COO- COO- COO- ⊕ 2- + P 2-O P NH O3P-O i 3 2 2- O - O3P-O COO - OH COO 2-O P-O OH 3 5-Enolpyruvylshikimic acid- Glyphosate OH EPSP-Synthase 3-phosphate (EPSP) Glyphosate is effective in killing a wide variety of plants, including grasses, broadleaf, and woody plants. It has a relatively small effect on some clover species. By volume, it is one of the most widely used herbicides. It is commonly used for agriculture, horticulture, and silviculture, as well as garden maintenance (including home use). Some crops have been genetically engineered to be resistant to glyphosate. Glyphosate was first sold by Monsanto under the tradename "Roundup". Mechanism of the EPSP synthase reaction ? -- the phosphate group is lost from PEP with cleavage of the C-O bond, not the P-O bond. -- If the enzymic reaction is carried out in D2O, then deuterium is incorporated into the product, and is found equally distributed between the E- and Z-positions in the enolpyruvyl group. 2 2 -- If [3- H2]PEP is used as substrate in H2O then H is lost in equal amounts from the E- und Z- positions in the enolpyruvyl group in the product. These observations have led to the proposal of an addition-elimination sequence, as shown below: 106 COO COO COO H CH2 2- O3P-O 2- O 2- OH O3P-O COO O3P-O EPSP-Synthase OH 2 OH OPO3 In one key experiment, the existence of the tetrahedral intermediate was proven. The enzyme (800µM) 13 +S3P (800µM) + 2-[ C]-PEP (1mM) was mixed for 5s, and then quenched with Et3N. Ion exchange chromatography of the resulting products gave a small amount of the intermediate that could be characterized. Glyphosate is a potent inhibitor of EPSP synthase. The inhibition ist competitive with respect to PEP (Ki = 1µM) but non-competitive with respect to S3P (Eur. J. Biochem. 1984, 143, 351). E + S ES E + P E + S ES E + P EI EI + S ESI E + S ES E + P ESI Crystallographic studies have revealed how the substrate, intermediate, and glyphosate bind at the active site of the enzyme. A substrate analogue Z-3-fluoro-PEP acts as a pseudosubstrate and forms a relatively stable tetrahedral intermediate that could be crystallized on the enzyme (Mol. Microbiol. 2004, 51, 963). Chorismate Mutase The chorismate mutase reaction involves formally a Claisen rearrangement. This reaction occurs at a 1 o measurable rate in aqueous solution even in the absence of the enzyme (t /2 in water at 50 C ≈ 90 min), but the reaction is accelarated about ≈106 fold by the enzyme : 107 COOH COO- Chorismate HOOC Mutase O O COO- OH Prephenic acid Chorismate OH The enzymic and the spontaneous reactions could proceed through either chair-like or boat-like transition states. The stereochemical consequences, however, are different: COO - COO O O COO- COO- boat-like TS COO- OH OH O -OOC - HO COO O COO- COO- chair-like TS O COO- OH OH The stereochemical course of both enzymic and spontaneous reactions has been studied, and both have been shown to proceed through chair-like transitions states (JACS, 1984, 106, 2701; JACS 1985, 107, 5306). Other kinetic and spectroscopic studies have shown that the enzymic reaction most likely is a more-or- less concerted pericyclic reaction.
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