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Structures of Some Important Gibberellins and Their Precursors, Derivatives, and Inhibitors of Gibberellin Biosynthesis
Valerie Sponsel, Biology Department, University of Texas, San Antonio, Texas, USA
By definition, all GAs possess either a tetracyclic (four-ringed) ent-gibberellane skeleton containing 20 carbon atoms (Web Figure 20.1.A), or a 20-nor-ent-gibberellane skeleton, which has only 19 carbon atoms because carbon-20 (C-20) has been lost.
|Web Figure 20.1.A The structure of ent-gibberellane. (Click image to enlarge.)|
Gibberellins that contain all 20 carbon atoms are referred to as C20-GAs. The first-formed GA in plants is GA12, a C20-GA whose structure is shown below (Web Figure 20.1.B, top). The other GAs have only 19 carbons because they have lost C-20 (blue, on structure of the C20-GA) by metabolism. These are referred to as C19-GAs, and the structure of one of them, GA9, is shown below (see Web Figure 20.1.B, bottom). In nearly all C19-GAs, the carboxyl at C-4 forms a lactone at C-10 (red, on structure of GA9).
|Web Figure 20.1.B The structures of GA12 and GA9. (Click image to enlarge.)|
Other structural modifications include the insertion of additional functional groups, the position and stereochemistry of which can have profound effects on biological activity. For example, in a C19-GA, the presence of a hydroxyl group at C-3 in the β-orientation (shown by a darkened wedge-shaped bond on structures) is required for high biological activity in bioassays that rely on stem growth (see Web Figure 20.1.B). A C19-GA possessing a hydroxyl group at C-3 in the α-orientation (α-orientation is denoted by a dotted wedge) has substantially less biological activity than its 3β-OH counterpart. Substitution at C-2 can also have very important consequences for biological activity. For instance, a biologically active C19-GA that acquires a hydroxyl group at C-2 will become inactive if the hydroxyl is in β-orientation, whereas 2α-hydroxylation is less detrimental to bioactivity. Therefore, 3β-hydroxylation activates a C19-GA, whereas 2β-hydroxylation is a deactivating mechanism.
It is assumed that the strict structural requirements for bioactivity reflect the necessary size and shape needed for binding to the receptor protein.
Interestingly—and not surprisingly—the most biologically active GAs were among the first to be discovered, namely GA1, GA3, GA4, and GA7. These GAs, all of which have intrinsic or inherent stem growth-promoting activity, are C19-GAs. They all possess a 4,10-lactone, a carboxylic acid (—COOH) at C-6, a hydroxyl group at C-3 in β-orientation, and do not have a hydroxyl group at C-2 in β-orientation.
|Web Figure 20.1.C The structures of GA4, GA1, GA7, and GA3. (Click image to enlarge.)|
The presence of a double bond between C-1 and C-2 (as in GA7 and GA3) may account for enhanced bioactivity of GA7 relative to GA4, and of GA3 relative to GA1, because GA7 and GA3 will not be metabolically deactivated by 2β-hydroxylation. Hence, GA7 and GA3 are expected to have more sustained growth-promoting activity than GA4 and GA1, respectively.
Gibberellins can also be converted into conjugates, most commonly with glucose. The linkage of the GA moiety to glucose occurs either via a hydroxyl group to produce a GA-O-glucosyl ether, or via the COOH at C-6 yielding a GA-glucosyl ether. When applied to bioassay plants, the GA-O-glucosyl ethers show little to no activity, indicating that they are deactivation products. The intact GA-glucosyl esters have no bioactivity, yet they may show biological activity if they are hydrolyzed within a bioassay plant yielding a free biologically active GA. Hence, the formation of glucosyl ester conjugates at a specific stage in the life cycle of a plant may be a mechanism for sequestration of bioactive GA that can be released later, as required.
Chemicals, either natural or synthetic, that interfere with GA biosynthesis usually retard growth. These types of chemicals, which are referred to as growth retardants, have been used for many years to reduce the height of plants in order to enhance yield of fruit or grain. The utility of growth retardants depends on their effectiveness to inhibit GA biosynthesis, their lack of toxicity, and on their specificity.
Discussion of GA biosynthesis in Web Topic 20.3 describes the types of enzymes involved in different stages of GA biosynthesis. Growth retardants have been produced that can target most of these different classes of enzymes. For example, compounds that contain a quaternary ammonium group have been developed to target the terpene synthases in stage 1, of which ent-copalyl diphosphate synthase (CPS) is an example (see Web Topic 20.3). Chlormequat chloride (also known as cycocel), mepiquat chloride and AMO-1618 (Web Figure 20.1.D) are thus all growth retardants blocking the synthesis of the GA-precursor ent-copalyl diphosphate. Chlormequat chloride is used extensively to reduce lodging in wheat, and to reduce vegetative growth in cotton.
|Web Figure 20.1.D The structures of chlormequat chloride (also known as cycocel), mepiquat chloride and AMO-1618. (Click image to enlarge.)|
Another type of GA biosynthesis inhibitor, the triazoles, of which paclobutrazol and uniconazole are examples (Web Figure 20.1.E ), inhibit the monooxygenase enzymes that catalyze stage 2 in GA biosynthesis (Web Topic 20.3). These growth retardants target ent-kaurene oxidase, thereby inhibiting the formation of ent-kaurenoic acid. They are used commercially to restrict the stem growth of fruit trees and ornamental plants.
|Web Figure 20.1.E The structures of paclobutrazol and uniconazole-P. (Click image to enlarge.)|
Dioxygenase enzymes catalyze the oxidative steps between individual C20- and C19-GAs in stage 3 (Web Topic 20.3). These enzymes utilize 2-oxoglutarate as a co-substrate, and so are competitively inhibited by compounds that resemble 2-oxoglutarate. Examples of this type of inhibitor are prohexadione calcium (BX-112) and daminozide (Web Figure 20.1.F). Most commonly, these inhibitors interfere with oxidation at C-20 or at C-3, and hence reduce the formation of bioactive GA. They are therefore effective growth retardants and can be used to retard the growth of potted ornamental plants.
|Web Figure 20.1.F The structures of prohexadione calcium (BX-112) and daminozide. (Click image to enlarge.)|
The last type of growth retardant to be considered here are analogs that interfere with the activity of dioxygenases by mimicking the GA-substrate rather than 2-oxoglutarate. One example of this type of inhibitor is a group of GAs in which the exocyclic methylene (=CH2) at C-16 is replaced by a methyl group. This type of substitution typically reduces activity of biologically active GA, and can also make them effective inhibitors of dioxygenase enzymes. For example, exo-16,17-dihydro-GA5, which is normally applied as the 13-acetate (Web Figure 20.1.G), is a very effective growth retardant for grasses but not for dicot species.
|Web Figure 20.1.G The structure of exo-16,17-dihydro-GA5 13-acetate.|
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