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首页> 外文期刊>Bioorganic and Medicinal Chemistry Letters >Carbonic anhydrase activators: X-ray crystal structure of the adduct of human isozyme II with L-histidine as a platform for the design of stronger activators.
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Carbonic anhydrase activators: X-ray crystal structure of the adduct of human isozyme II with L-histidine as a platform for the design of stronger activators.

机译：碳酸酐酶活化剂：人同工酶II加合物的X射线晶体结构，其中L-组氨酸为设​​计更强活化剂的平台。

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摘要

Activation of the carbonic anhydrase (CA, EC 4.2.1.1) isoforms hCA I, II, and IV with l-histidine and some of its derivatives has been investigated by kinetic and X-ray crystallographic methods. l-His was a potent activator of isozymes I and IV (activation constants in the range of 4-33microM), and a moderate hCA II activator (activation constant of 113microM). Both carboxy- as well as amino-substituted l-His derivatives, such as the methyl ester or the dipeptide carnosine (beta-Ala-His), acted as more efficient activators as compared to l-His. The X-ray crystallographic structure of the hCA II-l-His adduct showed the activator to be anchored at the entrance of the active site cavity, participating in an extended network of hydrogen bonds with the amino acid residues His64, Asn67, and Gln92 and, with three water molecules connecting it to the zinc-bound water. Although the binding site of l-His is similar to that of histamine, the first CA activator for which the X-ray crystal structure has been reported in complex with hCA II (Briganti, F.; Mangani, S.; Orioli, P.; Scozzafava, A.; Vernaglione, G.; Supuran, C. T. Biochemistry1997, 36, 10384) there are important differences of binding between the two structurally related activators, since histamine interacts among others with Asn67 and Gln92 (similarly to l-His), but also with Asn62 and not His64, whereas the number of water molecules connecting them to the zinc-bound water is different (two for histamine, three for l-His). Furthermore, the imidazole moieties of the two activators adopt different conformations when bound to the enzyme active site. Since neither the amino- nor carboxy moieties of l-His participate in interactions with amino acid moieties of the active site, they can be derivatized for obtaining more potent activators, with pharmacological applications for the enhancement of synaptic efficacy. This may constitute a novel approach for the treatment of Alzheimer's disease, aging, and other conditions in need of achieving spatial learning and memory therapy.
机译：已经通过动力学和X射线晶体学方法研究了用1-组氨酸及其某些衍生物活化碳酸酐酶（CA，EC 4.2.1.1）同工型hCA I，II和IV。 1-His是同工酶I和IV的有效激活剂（激活常数在4-33microM范围内），是中等的hCA II激活剂（激活常数113microM）。与1-His相比，羧基和氨基取代的1-His衍生物（例如甲酯或二肽肌肽（β-Ala-His））均是更有效的活化剂。 hCA II-1-His加合物的X射线晶体学结构表明，该激活剂锚定在活性位点腔的入口处，参与了与氨基酸残基His64，Asn67和Gln92和，三个水分子将其与结合锌的水相连。尽管I-His的结合位点与组胺的结合位点相似，但已报道了第一个CA活化剂，其X射线晶体结构与hCA II结合（Briganti，F .; Mangani，S .; Orioli，P. ; Scozzafava，A .; Vernaglione，G .; Supuran，CT Biochemistry1997，36，10384），由于两个组胺与Asn67和Gln92（类似于l-His）相互作用，因此两种结构相关的激活剂之间存在重要的结合差异，但是使用Asn62而不使用His64时，将它们连接到与锌结合的水的水分子数量却有所不同（组胺为两个，l-His为三个）。此外，当与酶活性位点结合时，两种活化剂的咪唑部分采用不同的构象。由于1-His的氨基或羧基均不参与与活性位点的氨基酸的相互作用，因此可以将它们衍生化以获得更有效的活化剂，并通过药理学应用来增强突触效力。这可能是治疗阿尔茨海默氏病，衰老和其他需要实现空间学习和记忆疗法的疾病的新颖方法。

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