We evaluated by the semiempirical method PM3 possible mechanisms of a putative interaction between a cereal allelochemical, the cyclic hydroxamic acid 2,4dihydroxy-7-metoxy-2H-1,4-benzoxazin-3(4H)-one (DIMBOA), and the tripeptide glutathione (GSH) inside the active site of a theta-class glutathione S-transferase. Based on a preliminary study of transition states from DIMBOA reactions with methanethiolate as a simple model of GSH, we investigated the roles of catalytic residues of the enzyme during nucleophilic additions of GSH to the carbonyl groups of DIMBOA and of its phenol/aldehyde isomer inside the active site model. Our results suggest that a tyrosine residue, Tyr113, makes the most important contributions for the catalytic mechanism. In the modeled reaction steps, Tyr113 behaves as a double hydrogen bond donor catalyst for nucleophilic additions of GSH to substrates: It initially helps stabilize the strongly nucleophilic reduced GSH with a hydrogen bond intermediated by a water molecule; during substrate approach, small conformational changes enable the residue to make a direct hydrogen bond to the substrate group that develop negative charge after addition of reduced GSH.
Recebido em 22/3/00; aceito em 5/2/01 A SEMIEMPIRICAL STUDY ON HYDROXAMIC ACIDS: FORMOHYDROXAMIC ACID AND DERIVATIVES OF THE ALLELOCHEMICAL DIMBOA. Open chain hydroxamic acid (Hx) can exist as Z and E diastereomers of two tautomers, hydroxamic acid and hydroximic acid. The conformational stability of the formohydroxamic acid isomers evaluated by PM3 compared better to ab initio results from the literature than AM1 results. Structural data of the cyclic Hx 2,4-dihydroxy-7-metoxy-2H-1,4-benzoxazin-3(4H)-one (DIMBOA) obtained by both semiempirical methods compared well to ab initio results. pK a data from the literature for derivatives of the aldolic isomer of DIMBOA were compared to the stability of the anions resulting from the loss of protons of their phenol and hydroxamic acid groups, determined as the difference in heat of formation between anionic and neutral forms, calculated by AM1 and PM3 methods. Good correlations between theoretical and experimental data were obtained for both semiempirical methods.Keywords: semiempirical; hydroxamic acids; acidity. Quim. Nova, Vol. 24, No. 5, 583-587, 2001. Artigo INTRODUÇÃOTodos os anos a produção mundial de grãos sofre grandes perdas, tanto em quantidade quanto em qualidade, devido à infestação por pragas, principalmente insetos. Além do custo elevado, o uso em larga escala de inseticidas sintéticos para o controle dos insetos tem resultado na perda de eficiência devido ao desenvolvimento de resistência pelos insetos e em efeitos danosos sobre o meio ambiente. A investigação dos mecanismos naturais de defesa das plantas contra organismos agressores é uma possível fonte de alternativas para o desenvolvimento de novas classes de inseticidas. As plantas produzem metabólitos secundários, chamados substâncias alelopáticas ou aleloquímicos, que atuam na sua defesa contra herbívoros, patógenos ou mesmo contra plantas competidoras 1 . Estudos têm demonstrado que ácidos hidroxâmicos (Hx) cíclicos do tipo 4-hidróxi-1,4-benzoxazin-3-onas (benzoxazinóides), presentes em cereais na forma de 2-β-O-D-glicosídeos, atuam sobre insetos, fungos e bactérias 2-5 . Os glicosídeos são biologicamente inativos, mas a ruptura das células vegetais libera β-glicosidases que degradam os glicosídeos enzimaticamente, liberando as agliconas tóxicas 6 . O Hx predominante no trigo e no milho é a 2,4-diidroxi-7-metoxi-1,4-benzoxazin-3-ona (DIMBOA, 1, Figura 1), isolada sob a forma do glicosídeo (2R)-2-β-glicopiranosiloxi-4-hidroxi-7-metoxi-2H-1,4-benzoxazin-3-ona 6 . Em solução aquosa, 1 está em equilíbrio com a forma aldólica 2 (Figura 1) 7 . A participação desse Hx na defesa do trigo contra insetos é sugerida pelo aumento de seus níveis na planta após infestação por afídios 3,5 e pelo seu efeito anti-alimentar em insetos alimentados com dietas artificiais contendo 1 8 . Existem várias indicações quanto aos possíveis sítios bioquímicos de ação dos áci-dos hidroxâmicos. Foi demonstrado que 1 inibe enzimas envolvidas na síntese de ATP 9 , a acilcolinaesterase (acilcolina hidrolase) 10 , a enzima destoxi...
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