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The structure of the substrate-free form of MurB, an essential enzyme for the synthesis of bacterial cell walls.
Structure. 1996 Jan 15; 4(1):47-54.S

Abstract

BACKGROUND

The repeating disaccharide and pentapeptide units of the bacterial peptidoglycan layer are connected by a lactyl ether bridge biosynthesized from UDP-N-acetylglucosamine and phosphoenolpyruvate in sequential enol ether transfer and reduction steps catalyzed by MurA and MurB respectively. Knowledge of the structure and mechanism of the MurB enzyme will permit analysis of this unusual enol ether reduction reaction and may facilitate the design of inhibitors as candidate next-generation antimicrobial agents.

RESULTS

The crystal structure of UDP-N-acetylenolpyruvylglucosamine reductase, MurB, has been solved at 3.0 A and compared with our previously reported structure of MurB complexed with its substrate enolpyruvyl-UDP-N- acetylglucosamine. Comparison of the liganded structure of MurB with this unliganded form reveals that the binding of substrate induces a substantial movement of domain 3 (residues 219-319) of the enzyme and a significant rearrangement of a loop within this domain. These ligand induced changes disrupt a stacking interaction between two tyrosines (Tyr190 and Tyr254) which lie at the side of the channel leading to the active site of the free enzyme.

CONCLUSIONS

The conformational change induced by enolpyruvyl-UDP-N- acetylglucosamine binding to MurB results in the closure of the substrate-binding channel over the substrate. Tyr190 swings over the channel opening and establishes a hydrogen bond with an oxygen of the alpha-phosphate of the sugar nucleotide substrate which is critical to substrate binding.

Authors+Show Affiliations

Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.No affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

8805513

Citation

Benson, T E., et al. "The Structure of the Substrate-free Form of MurB, an Essential Enzyme for the Synthesis of Bacterial Cell Walls." Structure (London, England : 1993), vol. 4, no. 1, 1996, pp. 47-54.
Benson TE, Walsh CT, Hogle JM. The structure of the substrate-free form of MurB, an essential enzyme for the synthesis of bacterial cell walls. Structure. 1996;4(1):47-54.
Benson, T. E., Walsh, C. T., & Hogle, J. M. (1996). The structure of the substrate-free form of MurB, an essential enzyme for the synthesis of bacterial cell walls. Structure (London, England : 1993), 4(1), 47-54.
Benson TE, Walsh CT, Hogle JM. The Structure of the Substrate-free Form of MurB, an Essential Enzyme for the Synthesis of Bacterial Cell Walls. Structure. 1996 Jan 15;4(1):47-54. PubMed PMID: 8805513.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The structure of the substrate-free form of MurB, an essential enzyme for the synthesis of bacterial cell walls. AU - Benson,T E, AU - Walsh,C T, AU - Hogle,J M, PY - 1996/1/15/pubmed PY - 1996/1/15/medline PY - 1996/1/15/entrez SP - 47 EP - 54 JF - Structure (London, England : 1993) JO - Structure VL - 4 IS - 1 N2 - BACKGROUND: The repeating disaccharide and pentapeptide units of the bacterial peptidoglycan layer are connected by a lactyl ether bridge biosynthesized from UDP-N-acetylglucosamine and phosphoenolpyruvate in sequential enol ether transfer and reduction steps catalyzed by MurA and MurB respectively. Knowledge of the structure and mechanism of the MurB enzyme will permit analysis of this unusual enol ether reduction reaction and may facilitate the design of inhibitors as candidate next-generation antimicrobial agents. RESULTS: The crystal structure of UDP-N-acetylenolpyruvylglucosamine reductase, MurB, has been solved at 3.0 A and compared with our previously reported structure of MurB complexed with its substrate enolpyruvyl-UDP-N- acetylglucosamine. Comparison of the liganded structure of MurB with this unliganded form reveals that the binding of substrate induces a substantial movement of domain 3 (residues 219-319) of the enzyme and a significant rearrangement of a loop within this domain. These ligand induced changes disrupt a stacking interaction between two tyrosines (Tyr190 and Tyr254) which lie at the side of the channel leading to the active site of the free enzyme. CONCLUSIONS: The conformational change induced by enolpyruvyl-UDP-N- acetylglucosamine binding to MurB results in the closure of the substrate-binding channel over the substrate. Tyr190 swings over the channel opening and establishes a hydrogen bond with an oxygen of the alpha-phosphate of the sugar nucleotide substrate which is critical to substrate binding. SN - 0969-2126 UR - https://www.unboundmedicine.com/medline/citation/8805513/The_structure_of_the_substrate_free_form_of_MurB_an_essential_enzyme_for_the_synthesis_of_bacterial_cell_walls_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0969-2126(96)00008-1 DB - PRIME DP - Unbound Medicine ER -