Researchers have discovered more than 200 splice variants in a class of enzymes known for its involvement in the synthesis of transfer RNAs, the aminocayl tRNA synthetases (AARSs). Most of those splice variants did not include the catalytic domains that are necessary for specifying tRNAs – a clear indication that their biological function has changed from that of the AARS family.

There are other enzymes whose functions can be broader than the catalytic domains they are named for. Some oncogenic kinases can drive cancer without their catalytic domain, and histone deacetylases can work in ways that have nothing to do with their epigenetic role. (See BioWorld Today, Dec. 2, 2013.)

But AARS "would have to be the gold medal family" of gene inserts, both for the sheer number of new domains and the diversity of their functions, John Mendlein told BioWorld Today.

Mendlein is CEO of Atyr Pharma Inc. and a co-author of the paper describing the new variants, which appeared in the July 18, 2014, issue of Science.

AARSs were already famous among biologists for acquiring more than a dozen new domains over their evolutionary history. But in the new work, the authors used advanced transcriptomes analysis to show that those previously identified extra domains were only the tip of the iceberg.

Senior author Paul Schimmel, who is at the Scripps Research Institute, said the AARS variants "represent a very important class of new protein therapeutics analogous to widely used injectable protein therapeutics" such as insulin, EPO, growth hormone and G-CSF.

Mendlein said the scientific theory of why adding domains to the AARS family has been such an evolutionary favorite is that its structure is amenable to such additions.

When you insert a new functionality into an existing gene, "two things can happen," he explained.

The first, and more likely, effect is that "you kill the organism," because there is a high likelihood that such insertions will disrupt the original function of the gene that finds itself the owner of such a new domain.

But if the original function is not disrupted, then the new domain has found a safe place for itself, precisely because the original gene function is important for the organism. Mendlein likened it to "a genetic Swiss bank account that can take very safe deposits."

AARS may be a particularly deposit-happy protein because it naturally exists in 20 splice variants to begin with – one for each amino acid.

Atyr is developing therapeutics that target AARS-derived proteins that do not play roles in tRNA synthesis, or protein synthesis more generally. "We're focusing on the regenerative and immunological mediators," Mendlein said, and specifically on the role of such mediators in rare diseases.

Furthest along is Resokine IV, which has completed phase I studies testing its potential as an immunomodulatory.

The company has dubbed those proteins physiocrines, and the Science paper, among other things, marks a roughly 20-fold expansion of known physiocrines. Mendlein said that for Atyr, the findings "could be a way of dividing up the biology" to make strategic decisions about which physiocrines to target. For example, a number of the newly identified physiocrines are expressed in the brain, and so the findings "could open the door to creating a partnership in neurodegeneration," Mendlein said.

For drug discovery, it is also important to know the mechanism of action for several reasons. In 2013, scientists at the University of Pennsylvania showed that some histone deacetylases work through other mechanisms than the epigenetic effects that give the enzyme class its name. (See BioWorld Today, Dec. 2, 2013.)

Although on one level, the proof is in the pudding, combination treatments can lead to unpleasant surprises if a drug works differently than its developers believe. Likewise, the development of optimized second-generation drugs depends on a clear understanding of the actual mechanism of action.