The liver biliverdin reductase reduces the biliverdins formed by heme degradation to bilirubins and the latter conjugated and excreted. Biliverdin reductase exists under the form of two isozymes in normal liver, the major form of which is transformed into a third isozyme in animals subjected to oxidative stress. The interconversion of one isozyme into the other is catalyzed by a peroxisomal NADH-dependent dehydrogenase whose induction mechanism and properties will be studied. The substrate specificity of biliverdin reductase will also be examined with the help of synthetic bilitrienes, to establish the liver capacity to reduce exogenous biliverdins as well as biliverdins formed from exogenously added hemins. These studies will allow to improve our understanding of the mechanism of the liver heme degradation processes. Studies on the mechanisms of uroporphyrinogen biosynthesis from porphobilinogen will be carried out to establish the nature of the intermediates of the process. 13C-NMR techniques have allowed to detect the formation of enzyme free transient intermediates in the enzymatic polymerization of porphobilinogen, to uroporphyrinogen, which differ in their structure and properties from those described by other research groups. This enzymatic reaction is the porphyrin making reaction of nature which is responsible for the synthesis of hemoglobin and hemoproteins in the metabolism, and whose derangement is the cause of many patologies. The function and properties of porphobilinogen oxygenase of bone marrow of rats will be studied to establish its involvement in the control of heme synthesis in erythropoietic tissues. The activity and inhibitory mechanisms of this enzyme at the different stages of the erythroid cell maturation in the bone marrow, and the comparison of its activity with porphobilinogen deaminase will unveil new molecular control mechanisms of heme synthesis in erythropoietic tissues. Pyrroles will be used as synthons for 1,4-diaminoalkanes (substituted putrescines) synthesis. This will allow to obtain a large number of selectively substituted putrescines with the ultimate end of studying their pharmacological antiproliferative effects.
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