On the development of new biocatalytic processes for practical pharmaceutical synthesis.

Natural enzymes have evolved to perform their cellular functions under complex selective pressures, which often require their catalytic activities to be regulated by other proteins. We contrasted a natural enzyme, LovD, which acts on a protein-bound (LovF) acyl substrate, with a laboratory-generated variant that was transformed by directed evolution to accept instead a small free acyl thioester and no longer requires the acyl carrier protein. The resulting 29-mutant variant is 1,000-fold more efficient in the synthesis of the drug simvastatin than the wild-type LovD. This is to our knowledge the first nonpatent report of the enzyme currently used for the manufacture of simvastatin as well as the intermediate evolved variants. Crystal structures and microsecond-scale molecular dynamics simulations revealed the mechanism by which the laboratory-generated mutations free LovD from dependence on protein-protein interactions. Mutations markedly altered conformational dynamics of the catalytic residues, obviating the need for allosteric modulation by the acyl carrier LovF.

/pdf/the-role-of-distant-mutations-and-allosteric-regulation-on-53wbasvt8y.pdf

The role of distant mutations and allosteric regulation on LovD active site dynamics

Biocatalysis, using enzymes for organic synthesis, has emerged as powerful tool for the synthesis of active pharmaceutical ingredients (APIs). The first industrial biocatalytic processes launched in the first half of the last century exploited whole-cell microorganisms where the specific enzyme at work was not known. In the meantime, novel molecular biology methods, such as efficient gene sequencing and synthesis, triggered breakthroughs in directed evolution for the rapid development of process-stable enzymes with broad substrate scope and good selectivities tailored for specific substrates. To date, enzymes are employed to enable shorter, more efficient, and more sustainable alternative routes toward (established) small molecule APIs, and are additionally used to perform standard reactions in API synthesis more efficiently. Herein, large-scale synthetic routes containing biocatalytic key steps toward >130 APIs of approved drugs and drug candidates are compared with the corresponding chemical protocols (if available) regarding the steps, reaction conditions, and scale. The review is structured according to the functional group formed in the reaction.

https://pubs.acs.org/doi/pdf/10.1021/acs.chemrev.1c00574

Shortening Synthetic Routes to Small Molecule Active Pharmaceutical Ingredients Employing Biocatalytic Methods

Highly engineered biocatalysts for efficient small molecule pharmaceutical synthesis.

The invention relates to a lovastatin acyltransferase mutant. The mutant contains an acyltransferase amino acid sequence represented by SEQIDNO.1 of wild A. terreus and at least 2-6 amino acid mutations selected from N45R, A110P, S145N, Q230M, L293M and L379M. The invention also relates to a nucleic acid nucleic acid for coding the mutant, a relevant expression vector, a host cell, and a use of the mutant in the synthesis of lovastatin.

Lovastatin acyltransferase containing one or more point mutations

The present disclosure provides acyltransferases useful for synthesizing therapeutically important statin compound

Variant LOVD polypeptides and their uses

Methods for the improved acylation of chemical substrates using LovD acyltransferases, thioesters having acyl groups, and (i) thiol scavengers and/or (ii) precipitating agents are presented. An improved method for the production of simvastatin using (i) activated charcoal as a thiol scavenger and/or (ii) ammonium hydroxide as a precipitating agent is also presented.

Improved lov-d acyltransferase mediated acylation

Methods for the improved acylation of chemical substrates using LovD acyltransferases, thioesters having acyl groups, and (i) thiol scavengers and/or (ii) precipitating agents are presented An improved method for the production of simvastatin using (i) activated charcoal as a thiol scavenger and/or (ii) ammonium hydroxide as a precipitating agent is also presented

Lov-D acyltransferase mediated acylation

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Variant LOVD polypeptides and their uses

Improved lov-d acyltransferase mediated acylation

Lov-D acyltransferase mediated acylation