The importance of L-Dopa decarboxylase as a metabolic participant in viral replication and pathogenesis

Postgraduate Thesis uoadl:2922626 12 Read counter

Κατεύθυνση Κλινική Βιοχημεία - Μοριακή Διαγνωστική
Library of the School of Science
Deposit date:
Chalari Anna
Supervisors info:
Διδώ Βασιλακοπούλου, Αναπληρώτρια καθηγήτρια, τμήμα Βιολογίας, Εθνικό και Καποδιστριακό Πανεπιστήμιο Αθηνών
Original Title:
Σημασία της L-Dopa αποκαρβοξυλάσης ως μεταβολικός παράγοντας καθοριστικός για την ιική αντιγραφή και παθογένεια
Translated title:
The importance of L-Dopa decarboxylase as a metabolic participant in viral replication and pathogenesis
DENV infection poses a life-threatening burden in tropical countries. Unfortunately, an effective vaccine or therapeutic agent for treating DENV infection with limited side effects on patients is unavailable to date. Infection with any of the DENV serotypes may be asymptomatic in the majority of cases or may result in a wide spectrum of clinical symptoms. However, an increasing number of dengue cases present neurological manifestations that may affect both the central and peripheral nervous systems. Interestingly, based on our previous report, we revealed an emerging bidirectional inverse relationship between DENV replication and L-Dopa decarboxylase (DDC), a PLP-dependent enzyme that catalyzes the biosynthesis of bioactive amines. DDC has a well-established role in neurotransmission and the enzyme has been purified from a variety of peripheral organs, including the liver, where its physiological significance is not yet fully understood. Recently we demonstrated the interaction between DDC and phosphatidylinositol 3-kinase (PI3K), which indicates the role of L-Dopa decarboxylase as a major participant in signal transduction regulation, governing cell proliferation and apoptosis processes.
As a confirmation of the bidirectional negative relationship between DDC and DENV infection, silencing and overexpression of DDC were studied for their putative effect on viral replication. Next, we sought to investigate a possible association between DENV propagation and the intracellular downstream metabolic pathway of dopamine and serotonin, that is their enzymatically induced oxidation by monoamine oxidases A and B (MAO A and B), which occurs concomitantly with the inevitable release of oxidized products. In addition, emphasis was given to vesicular monoamine transporters (VMATs) that protect biogenic amines from oxidation, through their storage in secretory vesicles and the putative role of oxidative stress on this intricate pathway.
Furthermore, a series of new 2-aminoalkylsubstituted 6-chloro- or 5,6-dichloro-1H-
imidazo[4,5-b]pyridines were synthesized, and evaluated as for their anti-HBV activity in an efficient infectious system. Hepatitis B virus (HBV) is the major causative factor of chronic hepatitis, liver cirrhosis and hepatocellular carcinoma (HCC), despite an efficient prophylactic vaccine. The most promising compounds underwent an in-depth study for defining the specific step of the viral life cycle targeted by the novel compounds.
Main subject category:
L-Dopa decarboxylase, DENV virus, Hepatitis B virus
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