Pathway analysis has also been used in studies involving secondary metabolism. “We look for families of genes that are associated with the biosynthesis of chemical compounds,” said Daniel Udwary, Ph.D., assistant professor, biomedical and pharmaceutical sciences, University of Rhode Island.
“We are interested in identifying new drugs from natural products and looking at various bacterial species based on their metabolomes. One particular feature of working with microbial metabolomes is that their genes are often clustered within an area in the genome. It is thus simply a matter of looking around that gene and the rest of the cluster is there; this also occurs in fungi, but not in plants and other higher-order organisms.”
Dr. Udwary’s research has concentrated on identifying gene clusters that are associated with the synthesis of secondary metabolites. “We have currently identified 3,892 gene clusters with specific pathways, and it is interesting to know that each pathway is different. It is almost the same as snowflakes, in which each one is unique. Now our challenge after identifying specific pathways is to be able to predict the mechanism of a specific gene based on its DNA sequence.”
Dr. Udwary plans to conduct comparative analyses of gene clusters among various microbial species to establish natural products-based drug discovery roadmaps.
“Unfortunately, drug discovery using natural products has diminished in the last few decades and a lot of potential mechanisms have been overlooked. It is critical for us to recognize that the horizontal transfer of genes plays an important role in the biosynthesis of new drugs, and thus revisiting these operons in microbial species can help in establishing trends in secondary metabolism.”
Pathway analysis has also helped scientists in elucidating mechanisms of drug action. According to Joshua Apgar, Ph.D., principal scientist of systems biology, department of immunology and inflammation at Boehringer Ingelheim Pharmaceuticals, their use of well-described pathway models has helped them understand drug selectivity and functionality.
“We are inspired by the fact that some compounds show functional selectivity in vivo but are not selective in vitro. We are interested in identifying on-target and off-target mechanisms of new drugs and how systems-level processes can affect these mechanisms,” explained Dr. Apgar.
These processes are quite complicated and may be influenced by a variety of feedback processes that only exist in vivo. Reconstruction of all these processes in vitro may be impossible and thus the use of pathway models has assisted their investigations of drug target effects.