This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Distribution of flux control between alcohol dehydrogenase (ADH) and ALDH liver ethanol metabolism We propose to quantify the distribution of control of the flux in the liver alcohol metabolism pathway between the many isoforms of alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH). The framework for the investigation will be Metabolic Control Analysis (MCA). For this investigation we will quantify the relative control of ADH and ALDH using the parallel tracks of in vitro assays of ADH and ALDH, in physiological buffer and computer simulations. We will determine the elasticities of the various forms of ADH and ALDH from human and horse livers. Further work will incorporate ALDH and kinetic studies on ALD and ALDH with vitamin A derivatives. The following specific aims will be studied: 1) To determine whether all forms of human class I ADH have equal elasticity with acetaldyhyde; 2) To determine whether all forms of human class I ADH and ALDH have equal elasticity to acetaldehyde; 3) To compare elasticity of ADH isoforms measured from in vitro assays with calculated rate constants; 4) To measure elasticities of all forms of ADH to retinoids in response to EtOH over the physiological range; 5) To measure elasticities of ALDH1 to retinoids with changes in EtOH over the physiological range; and 6) To determine the comparative elasticity between ALDH1 and ALDH11 to retionoids over the physiological range.
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