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The molecular basis of inhibition of Golgi alpha-mannosidase II by mannostatin A.

ABSTRACT: Mannostatin A is a potent inhibitor of the mannose-trimming enzyme, Golgi alpha-mannosidase II (GMII), which acts late in the N-glycan processing pathway. Inhibition of this enzyme provides a route to blocking the transformation-associated changes in cancer cell surface oligosaccharide structures. Here, we report on the synthesis of new Mannostatin derivatives and analyze their binding in the active site of Drosophila GMII by X-ray crystallography. The results indicate that the interaction with the backbone carbonyl of Arg876 is crucial to the high potency of the inhibitor-an effect enhanced by the hydrophobic interaction between the thiomethyl group and an aromatic pocket vicinal to the cleavage site. The various structures indicate that differences in the hydration of protein-ligand complexes are also important determinants of plasticity as well as selectivity of inhibitor binding.

SUBMITTER: Kuntz DA

PROVIDER: S-EPMC3956299 | biostudies-literature | 2009 Jan

REPOSITORIES: biostudies-literature

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The molecular basis of inhibition of Golgi alpha-mannosidase II by mannostatin A.

Kuntz Douglas A DA Zhong Wei W Guo Jun J Rose David R DR Boons Geert-Jan GJ

Chembiochem : a European journal of chemical biology 20090101 2

Mannostatin A is a potent inhibitor of the mannose-trimming enzyme, Golgi alpha-mannosidase II (GMII), which acts late in the N-glycan processing pathway. Inhibition of this enzyme provides a route to blocking the transformation-associated changes in cancer cell surface oligosaccharide structures. Here, we report on the synthesis of new Mannostatin derivatives and analyze their binding in the active site of Drosophila GMII by X-ray crystallography. The results indicate that the interaction with ...[more]

PMID: 19101978

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Project description:The development of effective inhibitors of Golgi α-mannosidase II (GMII, E.C.3.2.1.114) with minimal off-target effects on phylogenetically-related lysosomal α-mannosidase (LMan, E.C.3.2.1.24) is a complex task due to the complicated structural and chemical properties of their active sites. The pKa values (and also protonation forms in some cases) of several ionizable amino acids, such as Asp, Glu, His or Arg of enzymes, can be changed upon the binding of the inhibitor. Moreover, GMII and LMan work under different pH conditions. The pKa calculations on large enzyme-inhibitor complexes and FMO-PIEDA energy decomposition analysis were performed on the structures of selected inhibitors obtained from docking and hybrid QM/MM calculations. Based on the calculations, the roles of the amino group incorporated in the ring of the imino-D-lyxitol inhibitors and some ionizable amino acids of Golgi-type (Asp270-Asp340-Asp341 of Drosophila melanogaster α-mannosidase dGMII) and lysosomal-type enzymes (His209-Asp267-Asp268 of Canavalia ensiformis α-mannosidase, JBMan) were explained in connection with the observed inhibitory properties. The pyrrolidine ring of the imino-D-lyxitols prefers at the active site of dGMII the neutral form while in JBMan the protonated form, whereas that of imino-L-lyxitols prefers the protonation form in both enzymes. The calculations indicate that the binding mechanism of inhibitors to the active-site of α-mannosidases is dependent on the inhibitor structure and could be used to design new selective inhibitors of GMII. A series of novel synthetic N-substituted imino-D-lyxitols were evaluated with four enzymes from the glycoside hydrolase GH38 family (two of Golgi-type, Drosophila melanogaster GMIIb and Caenorhabditis elegans AMAN-2, and two of lysosomal-type, Drosophila melanogaster LManII and Canavalia ensiformis JBMan, enzymes). The most potent structures [N-9-amidinononyl and N-2-(1-naphthyl)ethyl derivatives] inhibited GMIIb (Ki = 40 nM) and AMAN-2 (Ki = 150 nM) with a weak selectivity index (SI) toward Golgi-type enzymes of IC50(LManII)/IC50(GMIIb) = 35 or IC50(JBMan)/IC50(AMAN-2) = 86. On the other hand, weaker micromolar inhibitors, such as N-2-naphthylmethyl or 4-iodobenzyl derivatives [IC50(GMIIb) = 2.4 μM and IC50 (AMAN-2) = 7.6 μM], showed a significant SI in the range from 111 to 812.

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The molecular basis of inhibition of Golgi alpha-mannosidase II by mannostatin A.

Publications

The molecular basis of inhibition of Golgi alpha-mannosidase II by mannostatin A.

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