A New Non‐Azole Inhibitor of ABA 8′‐Hydroxylase: Effect of the Hydroxyl Group Substituted for Geminal Methyl Groups in the Six‐Membered Ring.

Araki, Yoshiharu; Miyawaki, Arisa; Miyashita, Tomoyuki; Mizutani, Masaharu; Hirai, Nobuhiro; Todoroki, Yasushi

doi:10.1002/chin.200638073

Cited by 3 publications

(7 citation statements)

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“…Because the 3D structure of ABA 8'-hydroxylase has still not been investigated, we have attempted to explore the active site from the ligand side using many ABA analogues that we have developed. [19][20][21] In the process of this research, we found AHI1, a compound which can be a key molecule to uncover the mechanism of asymmetrical ligand recognition by ABA 8'-hydroxylase. AHI1 in addition to AHI1, and examined their binding potency to the ABA 8'-hydroxylase active site.…”

Section: Introductionmentioning

confidence: 96%

“…[10][11][12][13] Gene knockdown and overexpression studies suggest that ABA 8'-hydroxylase is a key enzyme for controlling ABA concentration during water deficit stress or dormancy maintenance and breaking. 14,15 To chemically control ABA 8'-hydroxylation in plants, we are developing stable ABA analogues [16][17][18] and specific inhibitors [19][20][21] against ABA 8'-hydroxylase. For effectively designing these chemicals, we need to know the substrate binding and enzyme reaction mechanisms in detail.…”

Section: Introductionmentioning

confidence: 99%

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Asymmetrical ligand binding by abscisic acid 8′-hydroxylase

Ueno

Yoneyama

Mizutani

et al. 2007

Bioorganic & Medicinal Chemistry

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Abscisic acid (ABA), a plant stress hormone, has a chiral center (C1') in its molecule, yielding the enantiomers (1'S)-(+)-ABA and (1'R)-(-)-ABA during chemical synthesis. ABA 8'-hydroxylase (CYP707A), which is the major and key P450 enzyme in ABA catabolism in plants, catalyzes naturally occurring (1'S)-(+)-enantiomer, whereas it does not recognize naturally not occurring (1'R)-(-)-enantiomer as either a substrate or an inhibitor. Here we report a structural ABA analogue (AHI1), whose both enantiomers bind to recombinant Arabidopsis CYP707A3, in spite of stereo-structural similarity to ABA. The difference of AHI1 from ABA is the absence of the side-chain methyl group (C6) and lack of the alpha,beta-unsaturated carbonyl (C2'C3'-C4'O) in the six-membered ring. To explore which moiety is responsible for asymmetrical binding by CYP707A3, we synthesized and tested ABA analogues that lacked each moiety. Competitive inhibition was observed for the (1'R) enantiomers of these analogues in the potency order of (1'R,2'R)-(-)-2',3'-dihydro-4'-deoxo-ABA (K(I)=0.45 microM)>(1'R)-(-)-4'-oxo-ABA (K(I)=27 microM)>(1'R)-(-)-6-nor-ABA and (1'R,2'R)-(-)-2',3'-dihydro-ABA (no inhibition). In contrast to the (1'R)-enantiomers, the inhibition potency of the (1'S)-analogues declined with the saturation of the C2',C3'-double bond or with the elimination of the C4'-oxo moiety. These findings suggest that the C4'-oxo moiety coupled with the C2',C3'-double bond is the significant key functional group by which ABA 8'-hydroxylase distinguishes (1'S)-(+)-ABA from (1'R)-(-)-ABA.

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Section: Introductionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

Asymmetrical ligand binding by abscisic acid 8′-hydroxylase

Ueno

Yoneyama

Mizutani

et al. 2007

Bioorganic & Medicinal Chemistry

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“…Although AHI4 did not exhibit ABA activity, it enhanced the effect of ABA with simultaneous treatment of both compounds in rice seedlings. Moreover, AHI4 induced drought stress tolerance in radish (Raphanus sativus) seedlings (Araki et al 2006). These results strongly suggested that AHI4 is an effective ABA catabolic inhibitor, although this report did not show whether AHI4 increased the endogenous amount of ABA.…”

Section: Aba Catabolic Inhibitorsmentioning

confidence: 95%

Chemical biology of abscisic acid

Kitahata

Asami

2011

J Plant Res

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Chemical biology is a discipline that utilizes chemicals to elucidate biological mechanisms and physiological functions. Various abscisic acid (ABA) derivatives have revealed the structural requirement for the perception by ABA receptors while biotin or caged derivatives of ABA have disclosed the localization of several ABA-binding proteins. Recently, selective ABA agonist has been used to identify ABA receptors. Furthermore, ABA biosynthesis and catabolic inhibitors have contributed to the identification of new ABA functions in plant growth and development. The physiological function of ABA in non-plant organisms has gradually been revealed. In this review, we discuss the development of small bioactive chemicals and their significance in ABA research.

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“…13,14 To chemically control ABA 8'-hydroxylation in plants, we are developing ABA analogues that function as competitive inhibitors against ABA 8'-hydroxylase. [15][16][17] AHI4, which was developed in a previous study, requires a very high concentration (> 400 μM) to confer drought tolerance by its exogenous application. 17 On the other hand, uniconazole (UNI), which is a well-known plant retardant developed in the 1980s, 18,19 strongly inhibits ABA 8'-hydroxylase both in vitro and in vivo.…”

mentioning

confidence: 99%

“…[15][16][17] AHI4, which was developed in a previous study, requires a very high concentration (> 400 μM) to confer drought tolerance by its exogenous application. 17 On the other hand, uniconazole (UNI), which is a well-known plant retardant developed in the 1980s, 18,19 strongly inhibits ABA 8'-hydroxylase both in vitro and in vivo. [20][21][22] Saito et al reported that UNI induces drought tolerance in Arabidopsis plants at 50 μM.…”

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confidence: 99%

Enlarged analogues of uniconazole, new azole containing inhibitors of ABA 8′-hydroxylase CYP707A

Todoroki

Aoyama

Hiramatsu

et al. 2009

Bioorganic & Medicinal Chemistry Letters

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We enlarged the uniconazole (UNI) molecule to find a specific inhibitor of abscisic acid (ABA) 8'-hydroxylase, and synthesized various UNI derivatives that were substituted with hydrophilic and hydrophobic groups at the 4-chlorine of the phenyl group of UNI using click chemistry. Considering its potency in ABA 8'-hydroxylase inhibition, its small effect on seedling growth, and its ease of application, UT4, the UNI derivative containing the C4 alkyltriazole, was the best candidate for a highly selective inhibitor of ABA 8'-hydroxylase.

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A New Non‐Azole Inhibitor of ABA 8′‐Hydroxylase: Effect of the Hydroxyl Group Substituted for Geminal Methyl Groups in the Six‐Membered Ring.

Cited by 3 publications

References 1 publication

Asymmetrical ligand binding by abscisic acid 8′-hydroxylase

Asymmetrical ligand binding by abscisic acid 8′-hydroxylase

Chemical biology of abscisic acid

Enlarged analogues of uniconazole, new azole containing inhibitors of ABA 8′-hydroxylase CYP707A

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