Urea: The Little Molecule that Could
Urea is a magical, symmetrical molecule, and reading Grether-Beck et al’s article transported me back in time, like Gil in Woody Allen’s movie “Midnight in Paris”. I visited two seminal years in urea’s history: 1828 and 1954.
In 1828 Friedrich Wohler synthesized urea in vitro, delivering a fatal blow to the concept of “vitalism” that suggested that life, and molecules that were products of living creatures, required more than chemistry (i.e., a vital force) for their synthesis.
Urea is easily quantified, and it was a focus for those studying the composition of sweat and epidermis. The 1954 state-of-the art thinking about urea and the skin is stated in Rothman’s text, Physiology and Biochemistry of the Skin. Imagine yourself a member of Rothman’s department at the University of Chicago, as were Fred Malkinson and Eugene Van Scott – two distinguished and current members of the Society for Investigative Dermatology.
Remember: In 1954, there was no molecular biology, no transgenic or knock-out animals, and no knockdown molecules. The Krebs-Henseleit urea cycle was described in 1932, and urea was known to be a synthesized by the liver to remove toxic ammonia resulting from protein catabolism. Clinicians used urea to treat multiple skin diseases (wounds just after the First World War and hand eczema in the 1930s) in addition to standby treatments such as tars and salicylic acid. Topical steroids were the new therapeutic superstar on the block. There was interest about urea’s high levels in the epidermis and sweat compared to those in the blood, and there was much speculation about the mechanisms responsible.
Fast forward to today and the experiments described by Grether-Beck. Two main groups of urea transporting molecules (UT-A1 and UT-A2) exist in the epidermis. These molecules have been knocked out in mice without obvious changes in epidermal structure or function. By contrast, knockouts of other epidermal molecules (e.g., p 63) are often associated with compromised neonatal epidermal barrier function, fluid loss, and death. Part of the reason may be that other molecules that transport urea, such as aquaphorin 3, may be quantitatively more important than the specific urea transporters in the epidermis.
One of the urea transporters of the UT-A2 group is the Kidd blood group. Humans lacking this protein have a grossly normal epidermis.
[Personal time machine moment: in 1957 I was working in a blood bank performing blood typing and was intrigued by the genetics of blood groups and writing my first article on the genetics of blood groups for the Columbia college medical student society magazine. What goes around comes around.]
Today, following the topical application of urea to the skin of healthy volunteers Grether-Beck report increased levels of the epidermal urea transporters, as well as increases in the antimicrobial properties of the epidermis. These results will no doubt inspire more detailed studies of urea metabolism in the epidermis and the investigation of new, urea-containing topicals.
In 1954 there was also high interest in the enzyme arginase, the terminal enzyme of the urea cycle, which converts arginine to ornithine (a precursor of polyamines) and urea. Arginase is measured at very high levels in normal human epidermis, but especially so in neoplastic epidermis. After a decades-long drought in studies of epidermal arginase, it appears a comeback is in progress.
Arginine is a substrate for inducible nitric oxide synthase (iNOS); its role as an immune modulator is the topic of a burgeoning research industry, and this will no doubt lead to further studies of arginase’s epidermal role (Munder, 2009). Connecting biochemistry and immunology illustrates the challenge of retaining broad knowledge while delving deeper and deeper into one’s personal scientific studies.
As the two hundredth anniversary of its in vitro synthesis approaches, urea will no doubt remain of interest to basic and clinical skin researchers and we expect future studies to seek optimal formulations of urea-containing drugs and explanations of how this small and simple molecule mediates its physiological and potential pharmaceutical roles in the epidermis.
I invite you to share your own time-travel moments with us.
Grether-Beck S, Felsner I, Brenden H, et al (2012): Urea Uptake Enhances Barrier Function and Antimicrobial Defense in Humans by Regulating Epidermal Gene Expression. J Invest Dermatol doi:10.1038/jid.2012.42
Munder,M (2009) Arginase:an emerging key player in the mammalian immune system. Br. J Pharm. 158:638-651