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Enzymes known as kinases play a critical role in cell growth, metabolism and signaling in a multitude of organisms across the tree of life—from algae to helminths to mammals. Now, scientists have developed an atlas of bacterial kinases and say their new compendium holds a motherlode of possible targets for reimagined antimicrobial drugs.

A team of researchers at the University of Georgia has zeroed in on serine-threonine kinases, regulators of cell growth and pathogenicity in a multitude of bacterial species. They say their compendium can provide guidance on research into bacterial virulence and potentially trailblazing ways to attack bacteria by inhibiting the activity of serine-threonine kinases. The team's compendium was developed by analyzing serine-threonine kinases in nearly 26,000 strains of bacteria.

"Bacterial serine-threonine kinases regulate diverse cellular processes associated with cell growth, virulence, and pathogenicity and are evolutionarily related to the druggable eukaryotic serine-threonine kinases," writes researcher Dr. Brady O'Boyle of the University of Georgia, lead author of the new study involving the massive atlas. O'Boyle and his team found that the number of serine-threonine kinases within bacterial genomes ranges from 1 in Escherichia coli to more than 60 in some species of Actinobacteria.

Humans are eukaryotes, and medical researchers have long exploited druggable serine-threonine kinases, a vast family of enzymes found in people and other mammals. Many serine-threonine kinases are implicated in diseases, making the enzymes ideal drug targets. Medications known as mTOR inhibitors are serine-threonine modulators, for example. The kidney cancer drug everolimus is an mTOR medication that inhibits serine-threonine kinase activity.

In the construction of the atlas, researchers relied on Hanks-type serine-threonine protein kinases, often referred to simply as serine-threonine kinases or simply protein kinases. These enzymes are part of a vast family that play crucial roles in metabolism, cell signaling, protein regulation, cellular transport, secretory processes, and other cellular pathways, O'Boyle and colleagues wrote.

In biological systems, serine-threonine kinases have a specific job: phosphorylating serine and threonine, which are amino acids within a protein chain. Phosphorylation refers to adding a phosphate group, usually from adenosine triphosphate (ATP), to a serine or threonine residue, thereby regulating protein functions.

Phosphorylation involving serine-threonine kinases is a pervasive form of biological regulation found across the tree of life. To assault bacteria in a new way, O'Boyle and colleagues suggest acting on druggable serine-threonine kinase sites, which could quell the organisms and possibly avoid the consequence of drug resistance.

In the journal Science Signaling, O'Boyle and colleagues report in detail how they analyzed hundreds of thousands of bacterial serine-threonine kinases and classified them into kinase and pseudokinase families based on shared similarities in their catalytic domains.

"A deeper understanding of how bacterial serine-threonine differ from their eukaryotic counterparts and how they have evolved to regulate diverse bacterial signaling functions is crucial for advancing the discovery and development of new antibiotic therapies," O'Boyle wrote.

The team classified more than 300,000 bacterial serine-threonine kinase sequences from the National Center for Biotechnology Information's reference sequence (RefSeq) of nonredundant protein databases.

Already, O'Boyle and collaborators see a way to use the compendium to address the tuberculosis bacterium in a new way. Biochemical and peptide library screens have suggested that inhibiting serine-threonine enzymatic activity may be a way to control Mycobacterium tuberculosis.

Overall, the findings open previously unidentified avenues for investigating bacterial serine-threonine kinase functions in cellular signaling and for developing selective bacterial serine-threonine kinase inhibitors. The giant compendium reads like a book with sections and headings, its developers say, underscoring that the atlas will aid researchers studying specific bacteria and enzymatic groups.

"The enzymes were broken into 35 canonical and seven pseudokinase families on the basis of the patterns of evolutionary constraints in the conserved catalytic domain and flanking regulatory domains," O'Boyle noted.

"Through statistical comparisons, we identified features distinguishing bacterial serine-threonine kinases from eukaryotic serine-threonine kinases, including an arginine residue in a regulatory helix (C helix) that dynamically couples the ATP- and substrate-binding lobes of the kinase domain," O'Boyle added.

While the atlas essentially classifies these thousands of enzymes into various families, it also provides a resource that can inform the study of kinase evolution. Yet, the biggest potential, its developers say, rests in its potential to help address the crisis in drug resistance.

"The structure and regulatory features we have presented in this paper […] could also be used to inform the development of broad-spectrum [bacterial serine-threonine kinase]-targeting antimicrobial drugs," O'Boyle and colleagues concluded.

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