Anewdiseaseprocess?chemiexcitation?hasbeenfoundtocontributetomelanoma,promptingthecurrent proposal to understand its chemistry and determine its role in additional skin disorders such as excessive scarringinburnwoundsortissuedeathafteratemporarylossofbloodsupply.Chemiexcitationisthechemical excitation of an electron to a high-energy quantum state. This process underlies the bioluminescence of a firefly, but it had never been seen in mammals. Recently researchers discovered that, in the skin cells that provide skin and hair color (melanocytes), sunlight's ultraviolet radiation (UV) activates two enzymes to synthesizethefreeradicalsnitricoxideandsuperoxide.Thesecombinetoformperoxynitrite,astrongoxidant thatisoneofthefewbiologicalmoleculesabletoexciteanelectrontoahighenergystate.Peroxynitritethen creates a strained dioxetane ring (C?O?O?C) on fragments of melanin pigment. The ring spontaneously breakstoyieldtwocarbonyls(C=O).Onecarbonylacquirestheenergy?thechemiexcitationstep?andends inaquantumtripletstatethathastheenergyofaUVphotonbuttransfersthisenergydirectlytoDNA.There, theenergycreatescyclobutanepyrimidinedimers(CPDs),atypeofDNAdamagethatleadstomutations,cell death,andalteredcellbehavior.Thisprocesscancontinueforhoursafterapersonleavesthebeach,making melanin carcinogenic as well as protective. Yet inflammation and temporary blood loss can also create nitric oxideandsuperoxide,raisingthepossibilitythatchemiexcitation'sroleindiseaseextendswellbeyondsunlight andcancer. The present proposal seeks to solidify biologists' understanding of chemiexcitation events within skin and explore how the same events can be triggered without UV. The project has three aims: 1) Determine the photo-enzymatic signaling steps that initiate chemiexcitation. 2) Elucidate the unsolved biochemical steps in melanocytechemiexcitation,seekmoleculesbesidesmelaninthatcanhostchemiexcitation,andidentifygenes underlying the variation in response between people. 3) Determine whether skin inflammation can substitute for UV and whether chemiexcitation therefore plays a role in hypertrophic scarring and ischemia-reperfusion injury. The results will put chemiexcitation on a firm footing in the setting of skin, and will provide a basis for investigatingtriplet-stateenergyquenchersthatdissipatethehighenergyasheatbeforeitcanleadtodisease.
/Relevance Thesestudiesexplorethephysico-chemicalmechanismandbiologicalconsequencesofarecentlyrecognized and potentially common pathogen: carbonyl groups containing excited electrons. High-energy carbonyls in melanin create cyclobutane pyrimidine dimers ? a DNA lesion known to be lethal, mutagenic, differentiation- altering,andacarcinogeninskin.Thisknowledgewillallowustoidentifydisordersthatthisprocesscausesand drugsthatcandissipatethehighenergyasheat,preventingdisease.
| Brash, Douglas E; Goncalves, Leticia C P; Bechara, Etelvino J H et al. (2018) Chemiexcitation and Its Implications for Disease. Trends Mol Med 24:527-541 |
