Process for cellular production of biologically active compounds

Abstract

A process of increasing the cellular production of biologically active compounds is provided. The process is particularly useful for increasing antibiotic production by bacterial cells. The process includes the step of inhibiting the activity of methylmalonyl-CoA mutase.

35 - 38 . (canceled) 
     
     
         39 . A method of increasing the production of a methylmalonyl-CoA or a derivative thereof, the method comprising reducing co-enzyme B 12  use by inhibition of at least one of a cob(I) alamin adenosyltransferase function or a methylmalonyl-CoA mutase function in a bacterium that produces at least one of a polyketide or a macrolide from methylmalonyl-CoA,
 wherein the production of methylmalonyl-CoA or a derivative thereof is increased when compared to production of methylmalonyl-CoA or the derivative thereof by a corresponding bacterium wherein co-enzyme B 12  use is not reduced.   
     
     
         40 . The method of  claim 39 , wherein the bacterium is selected from the group consisting of  Aeromicrobium erythreum  and  Saccharopolyspora erythraea.    
     
     
         41 . The method of  claim 40 , wherein the methylmalonyl-CoA derivative comprises at least one of a polyketide or a macrolide. 
     
     
         42 . The method of  claim 41 , wherein the inhibition of the cob(I) alamin adenosyltransferase function comprises disrupting a cob(I) alamin adenosyltransferase gene. 
     
     
         43 . The method of  claim 42 , wherein the inhibition of the methylmalonyl-CoA mutase function comprises disrupting a methylmalonyl-CoA mutase gene. 
     
     
         44 . The method of  claim 41 , wherein the at least one of a polyketide or a macrolide is selected from the group consisting of erythromycin, tylosin, niddamycin, spiramycin, oleandomycin, methymycin, neomethymycin, narbomycin, pikromycin, and lankamycin. 
     
     
         45 . A method of increasing the production of a methylmalonyl-CoA or a derivative thereof, the method comprising inhibiting a cob(I) alamin adenosyltransferase function in a bacterium that produces at least one of a polyketide or a macrolide from methylmalonyl-CoA by disruption of a cob(I) alamin adenosyltransferase gene,
 wherein the production of the methylmalonyl-CoA or a derivative thereof is increased when compared to production of methylmalonyl-CoA or the derivative thereof by a corresponding bacterium wherein the function of cob(I) alamin adenosyltransferase is not inhibited.   
     
     
         46 . The method of  claim 45 , wherein the bacterium is selected from the group consisting of  Aeromicrobium erythreum  and  Saccharopolyspora erythraea.    
     
     
         47 . The method of  claim 46 , wherein the methylmalonyl-CoA derivative comprises a polyketide or a macrolide. 
     
     
         48 . The method of  claim 47 , wherein the polyketide or a macrolide is selected from the group consisting of erythromycin, tylosin, niddamycin, spiramycin, oleandomycin, methymycin, neomethymycin, narbomycin, pikromycin, and lankamycin. 
     
     
         49 . The method of  claim 47 , wherein the polyketide is selected from the group consisting of rapamycin, FK520, candicidin, soraphen, ascomycin, and avernectin. 
     
     
         50 . The method of  claim 47 , wherein inhibiting cob(I) alamin adenosyltransferase function reduces the level of a co-factor necessary for methylmalonyl-CoA mutase activity. 
     
     
         51 . The method of  claim 50 , wherein the co-factor comprises coenzyme B 12 . 
     
     
         52 . A method of increasing the production of a methylmalonyl-CoA or a derivative thereof, the method comprising inhibiting a methylmalonyl-CoA mutase function in a bacterium that produces at least one of a polyketide or a macrolide from methylmalonyl-CoA by disruption of a methylmalonyl-CoA mutase gene,
 wherein the production of methylmalonyl-CoA or a derivative thereof is increased when compared to production of methylmalonyl-CoA or the derivative thereof by a corresponding bacterium wherein the function of methylmalonyl-CoA mutase is not inhibited.   
     
     
         53 . The method of  claim 52 , wherein the bacterium is selected from the group consisting of  Aeromicrobium erythreum  and  Saccharopolyspora erythraea.    
     
     
         54 . The method of  claim 53 , wherein the methylmalonyl-CoA derivative comprises at least one of a polyketide or a macrolide. 
     
     
         55 . The method of  claim 54 , wherein the polyketide is selected from the group consisting of rapamycin, FK520, candicidin, soraphen, ascomycin, and avermectin. 
     
     
         56 . The method of  claim 54 , wherein the at least one of a polyketide or a macrolide is selected from the group consisting of erythromycin, tylosin, niddamycin, spiramycin, oleandomycin, methymycin, neomethymycin, narbomycin, pikromycin, and lankamycin. 
     
     
         57 . The method of  claim 53 , wherein the methylmalonyl-CoA derivative comprises a feed growth promotant comprising monensin A or monensin B. 
     
     
         58 . The method of  claim 53 , wherein the methylmalonyl-CoA derivative comprises a plurality of methylmalonyl-CoA subunits.