Dynamics of tyrosine hydroxylase mediated regulation of dopamine synthesis

Abstract

Tyrosine hydroxylase's catalysis of tyrosine to dihydroxyphenylalanine (DOPA) is the highly regulated, rate-limiting step catalyzing the synthesis of the catecholamine neurotransmitter dopamine. Phosphorylation, cofactor-mediated regulation, and the cell's redox status, have been shown to regulate the enzyme's activity. This paper incorporates these regulatory mechanisms into an integrated dynamic model that is capable of demonstrating relative rates of dopamine synthesis under various physiological conditions. Most of the kinetic equations and substrate parameters used in the model correspond with published experimental data, while a few which were not available in literature have been optimized based on explicit assumptions. This kinetic pathway model permits a comparison of the relative regulatory contributions made by variations in substrate, phosphorylation, and redox status on enzymatic activity and permits predictions of potential disease states. For example, the model correctly predicts the recent observation that individuals with haemochromatosis and having excessive iron accumulation are at increased risk for acquiring Parkinsonism, a defect in neuronal dopamine synthesis (Bartzokis et al., 2004; Costello et al., 2004). Alpha synuclein mediated regulation of tyrosine hydroxylase has also been incorporated in the model, allowing an insight into the overexpression and aggregation of alpha synuclein in Parkinson's disease.

In silico evidence for glutathione- and iron-related pathogeneses in Parkinson's disease

“…These glutathione vulnerabilities are also consistent with dynamical models reported by Vali et al (2007), as our previous findings (Sass et al, 2009) support various other computational models in the parkinsonian literature (Raichur et al, 2006;Kaushik et al, 2007;Lecca, 2008).…”

“…After developing a working system, some known biochemical interactions of PD were introduced to comparatively reproduce the stages of neurodegeneration (Section 2.3). These canonical conventions of in silico modeling are becoming widely popular for system characterization, especially in the study of complex neurodegenerative diseases for their inherent application of elucidating and proposing pathogenic mechanisms for prospective, non-computational investigations (Raichur et al, 2006;Kaushik et al, 2007;Vali et al, 2007;Lecca, 2008).…”

A pragmatic approach to biochemical systems theory applied to an α-synuclein-based model of Parkinson's disease

“…Other approaches that would be well suited for comparisons to the model include gene expression analysis techniques such as Northern blots and RNA expression microarrays, and data from other biochemical models. Papers produced by the Voit group at Emory University and the Gorin group at UC Davis offer data from dynamic modeling studies on dopamine metabolism and ␣-synuclein aggregation (Raichur et al, 2006;Kaushik et al, 2007;Qi et al, 2008). Still, the literature largely lacks modeling data relevant to PD.…”

Iron regulation in C57BL/6 and DBA/2 mice subjected to iron overload

“…Iron plays a crucial role in several central biological processes including neurotransmitter synthesis, myelination and brain energy metabolism (Harley et al 1993;Beard 2003;Beard et al 2003;Ortiz et al 2004;Kaushik et al 2006). Thus, brain iron regulation is essential for normal biological functioning, and these homeostatic processes protect the brain from iron deficiency or overload.…”