The Structure of Streptomyces wadayamensis MppR
Mentor 1
Nicholas R. Silvaggi
Location
Union Wisconsin Room
Start Date
24-4-2015 2:30 PM
End Date
24-4-2015 3:45 PM
Description
Antibiotic discovery has slowed dramatically, while the occurrence of antibiotic-resistant infections is increasing. The microbial world has furnished modern medicine with a remarkable array of antibiotic compounds. Many of the most important drugs in the clinic are themselves, or are derived from, chemicals naturally produced by bacteria and fungi. For every viable antibiotic, however, there are many promising compounds that ultimately fail to become drugs. One such compound is mannopeptimycin (MPP), a cyclic glycopeptide antibiotic produced by Streptomyces wadayamensis that has potent activity against problematic pathogens like methicillin-resistant Staphylococcus aureus (MRSA). Mannopeptimycin has not become a clinically-viable antibiotic because it is too toxic to mammalian cells. In theory, it might be possible to develop analogs of mannopeptimycin, but these efforts are hampered by the fact that a key part of the pharmacophore of MPP, the non-proteinogenic amino acid L-enduracididine (L-End) is not commercially available and is very difficult to produce synthetically. Without this key building block, it is difficult to make MPP analogs. To address this problem, our lab is studying how S. wadayamensis produces L-End. The biosynthetic pathway is thought to originate from arginine and involves the action of three enzymes: MppP, MppQ, and MppR. None of these enzymes have a known biochemical function. We have determined the structure of MppR, which shows that its overall structure is very similar to that of acetoacetate decarboxylase. However, MppR does not display decarboxylase activity with acetoacetate or any alpha- or beta-keto acid we tested. Thus, more work is needed to identify the role of MppR in the production of L-End. /
The Structure of Streptomyces wadayamensis MppR
Union Wisconsin Room
Antibiotic discovery has slowed dramatically, while the occurrence of antibiotic-resistant infections is increasing. The microbial world has furnished modern medicine with a remarkable array of antibiotic compounds. Many of the most important drugs in the clinic are themselves, or are derived from, chemicals naturally produced by bacteria and fungi. For every viable antibiotic, however, there are many promising compounds that ultimately fail to become drugs. One such compound is mannopeptimycin (MPP), a cyclic glycopeptide antibiotic produced by Streptomyces wadayamensis that has potent activity against problematic pathogens like methicillin-resistant Staphylococcus aureus (MRSA). Mannopeptimycin has not become a clinically-viable antibiotic because it is too toxic to mammalian cells. In theory, it might be possible to develop analogs of mannopeptimycin, but these efforts are hampered by the fact that a key part of the pharmacophore of MPP, the non-proteinogenic amino acid L-enduracididine (L-End) is not commercially available and is very difficult to produce synthetically. Without this key building block, it is difficult to make MPP analogs. To address this problem, our lab is studying how S. wadayamensis produces L-End. The biosynthetic pathway is thought to originate from arginine and involves the action of three enzymes: MppP, MppQ, and MppR. None of these enzymes have a known biochemical function. We have determined the structure of MppR, which shows that its overall structure is very similar to that of acetoacetate decarboxylase. However, MppR does not display decarboxylase activity with acetoacetate or any alpha- or beta-keto acid we tested. Thus, more work is needed to identify the role of MppR in the production of L-End. /
