Do human lipoxygenases have a PDZ regulatory domain?
Human lipoxygenases and products of their catalytic reaction have a well established connection to many human diseases. Despite their importance in inflammation, cancer, cardiorenal and other ailments the drug development is impaired by the lack of structural details to understand their intricate specificity and function in molecular and cellular signaling. The major effort so far has been directed towards understanding the determinants of their specificity and inhibition of their active site with the iron cofactor. Their structure is believed to consist of only two domains: one regulatory - a beta-sandwich, important for membrane binding, and one, mostly helical, catalytic domain. Although recently published cohort studies on single nucleotide polymorphism and occurrence of diseases, SAXS analysis and new biochemical data throw new light on lipoxygenase suggesting symbiosis of regulatory functions with an allosteric mechanism and more flexible structure than anticipated. The goal of this brief review is to direct an attention to the structural features of an anticipated topology and stimulate discussion/research to prove or disapprove our hypothesis that lipoxygenases may possess about approximately 110 amino acids PDZ-like fragments of functional importance. If they do have a second regulatory domain, it might help to explain their association with other molecules, role in signaling pathways and present a new avenue to explore the regulation of their behavior, and thus intervention in the course of diseases.
Jankun
Jerzy
J
Urology Research Center, Department of Urology, Health Science Campus, University of Toledo, 3000 Arlington Ave., Toledo, OH 43614, USA.
Doerks
Tobias
T
Aleem
Ansari M
AM
Lysiak-Szydłowska
Wiesława
W
Skrzypczak-Jankun
Ewa
E
D000595:Amino Acid Sequence; D006801:Humans; D008084:Lipoxygenase / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D054731:PDZ Domains / Q000235:genetics; D017386:Sequence Homology, Amino Acid
D008084:Lipoxygenase