The
urea cycle and
nitric oxide cycle play significant roles in complex biochemical and physiologic reactions. These cycles have distinct biochemical goals including the clearance of waste
nitrogen; the production of the intermediates
ornithine,
citrulline, and
arginine for the
urea cycle; and the production of
nitric oxide for the
nitric oxide pathway. Despite their disparate functions, the two pathways share two
enzymes,
argininosuccinic acid synthase and
argininosuccinic acid lyase, and a transporter,
citrin. Studying the gene expression of these
enzymes is paramount in understanding these complex biochemical pathways. Here, we examine the expression of genes involved in the
urea cycle and the
nitric oxide cycle in a panel of eleven different tissue samples obtained from individual adults without known
inborn errors of metabolism. In this study, the pattern of co-expressed
enzymes provides a global view of the metabolic activity of the
urea and
nitric oxide cycles in human tissues. Our results show that these transcripts are differentially expressed in different tissues. Using the co-expression profiles, we discovered that the combination of expression of
enzyme transcripts as detected in our study, might serve to fulfill specific physiologic function(s) including
urea production/
nitrogen removal,
arginine/
citrulline production,
nitric oxide production, and
ornithine production. Our study reveals the importance of studying not only the expression profile of an
enzyme of interest, but also studying the expression profiles of the other
enzymes involved in a particular pathway so as to better understand the context of expression. The tissue patterns we observed highlight the variety of important functions of these
enzymes and provides insight into the many clinical observations that result from their disruption. These results have implications for the management of
urea cycle patients and raise considerations for the care of those patients receiving
liver transplants. Finally, this work reaffirms the concept that the co-expression of a few genes can significantly impact complex biochemical and physiologic processes.