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J. Biol. Chem., Vol. 279, Issue 13, 12369-12378, March 26, 2004

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Revisiting the Structure of the Anti-neoplastic Glucans of Mycobacterium bovis Bacille Calmette-Guérin

STRUCTURAL ANALYSIS OF THE EXTRACELLULAR AND BOILING WATER EXTRACT-DERIVED GLUCANS OF THE VACCINE SUBSTRAINS^*

Premkumar Dinadayala, Anne Lemassu, Pierre Granovski, Stéphane Cérantola, Nathalie Winter, and Mamadou Daffé¶

From the Département Mécanismes Moléculaires des Infections Mycobactériennes, Institut de Pharmacologie et Biologie Structurale, UMR 5089 du CNRS et de l'Université Paul Sabatier, 205 route de Narbonne, 31077 Toulouse cedex 04, France and Unité de Génétique Mycobactérienne, Institut Pasteur, 25 rue du Docteur Roux, 75724 Paris cedex 15, France

The attenuated strain of Mycobacterium bovis Bacille Calmette-Guérin (BCG), used worldwide to prevent tuberculosis and leprosy, is also clinically used as an immunotherapeutic agent against superficial bladder cancer. An anti-tumor polysaccharide has been isolated from the boiling water extract of the Tice substrain of BCG and tentatively characterized as consisting primarily of repeating units of 6-linked-glucosyl residues. Mycobacterium tuberculosis and other mycobacterial species produce a glycogen-like -glucan composed of repeating units of 4-linked glucosyl residues substituted at some 6 positions by short oligoglucosyl units that also exhibits an anti-tumor activity. Therefore, the impression prevails that mycobacteria synthesize different types of anti-neoplastic glucans or, alternatively, the BCG substrains are singular in producing a unique type of glucan that may confer to them their immunotherapeutic property. The present study addresses this question through the comparative analysis of -glucans purified from the extracellular materials and boiling water extracts of three vaccine substrains. The polysaccharides were purified, and their structural features were established by mono- and two-dimensional NMR spectroscopy and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry of the enzymatic and chemical degradation products of the purified compounds. The glucans isolated by the two methods from the three substrains of BCG were shown to exhibit identical structural features shared with the glycogen-like -glucan of M. tuberculosis and other mycobacteria. Incidentally, we observed an occasional release of dextrans from Sephadex columns that may explain the reported occurrence of 6-substituted -glucans in mycobacteria.

Received for publication, August 12, 2003 , and in revised form, January 9, 2004.

^* The work was supported in part by European Community Grant QLK2-CT-1999-01093). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed. Tel.: 33-561-175-569; Fax: 33-561-175-580; E-mail: mamadou.daffe{at}ipbs.fr.

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