The study showing that the proteins that maintaining the formicamycin biosynthesis fidelity; Formicamycins are a set of antibiotics produced by the bacteria Streptomyces formicae that have showing useful activity against antibiotic resistant strains of the pathogenic bacteria Staphyloccus aureus. But the machinery responsible for making the formicamycins can sometimes misfire leading to the production of minor shunt metabolites called the formicapyridines at very low levels.
Tests showing that isolating formicapyridines do not display antifungal or antibacterial activity. So why are they producing; The team who discovered the formicapyridines; were intriguing by the presence of these unusual molecules lacking anti-infective activity. Under certain environmental conditions, production of these molecules gave a selection advantage to Streptomyces formicae; could the organism adapt (evolve) rapidly, maybe even through a single mutation; to produce much higher levels of the formicapyridines.
Formicamycin biosynthesis fidelity
To test this possibility, and based on their prediction for how the formicapyridines are made, the team attempted to mimic the imagined adaptation mutations by introducing targeted gene; deletions to the formicamycin biosynthetic gene cluster. They predicted that one of these mutations would increase the levels of formicapyridines and, at the same time, abolish production of the formicamycin antibiotics.
In fact, although one mutant did increase formicapyridine production 25-fold, it did not abolish formicamycin production. Rather, the level of formicamycins was decreasing by approximately two thirds. This raising the next intriguing question; it is the role of the protein encoding by the deleting gene. We hypothesise that, rather than acting as a biosynthetic enzyme as we had presuming; this specific protein acts as a chaperone, or fidelity factor, that ensures that the biosynthetic process proceeds efficiency and does not give side products.
Substrates for housekeeping enzymes
These hypothetical intermediates would exist freely in solution or bound to enzymes in the case of assembly line processes; and eventually all flux through the pathway would end and only the final product would exist. In reality no pathways proceeding in this manner as the situation is complicating; by varying rates of reaction for the different steps, meaning that some intermediates accumulate; while the inherent reactivity of other intermediates, or their ability to act as substrates for housekeeping enzymes not dedicated to the pathway; means that shunt metabolites often arise.
The research has opened the route for others to test if the same hypothesis; applying to relating proteins in other organisms; that produce similar families of antibiotics. Matters are further complicated by the fact that pathways are often convergent, with multiple units made in parallel before assembly into the final product; for example in the biosynthetic pathways to macrolide or aminoglycoside antibiotics. A role for antibiotic biosynthesis monooxygenase domain proteins in fidelity control during aromatic polyketide biosynthesis.