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Dynamics of tyrosine hydroxylase mediated regulation of dopamine synthesis

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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 over-expression and aggregation of alpha synuclein in Parkinson's disease.

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Acknowledgments

PK and SV are employees of Cellworks Group Inc. (www.cellworksgroup.com) and SV is the chief scientific officer of Cellworks. Fredric Gorin is a scientific technical advisor for Cellworks. We would like to thank K.S. Ramanujan (Chief technical officer of Cellworks) and Rajtarun Madangopal for their critical insights into the computational aspects of the model.

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  1. Cellworks Group Inc., 13962 Pierce Road, Saratoga, CA, 95070, USA

    Poorvi Kaushik & Shireen Vali

  2. Department of Neurology and the Center for Neuroscience, University of California Davis, Davis, CA, 95616,, USA

    Fredric Gorin

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  1. Poorvi Kaushik
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Appendix 1: Calculation of activation constant of alpha synuclein

Appendix 1: Calculation of activation constant of alpha synuclein

$$ V_{{\max }_{\rm app}} = V_{\max} (1 + [{\rm Alpha}\,{\rm Synuclein}]/{\rm Ka}) $$

Where, \( V_{\max _{{\rm app}} }\) is the maximum velocity attained after activation by alpha Synuclein Vmax is the maximum velocity of dephosphorylation at endogenous levels of alpha Synuclein (negligible),

We know that activity of PP2A was doubled on addition of 100 nM Alpha Synuclein (Peng et al., 2005 )

$$ \Rightarrow V_{\max _{{\rm app}} } = {\rm }2 * V_{\max } $$
$$ 2 * V_{\max } {\rm } = {\rm }V_{\max } (1 + 100\,{\rm nM}/{\rm Ka}) $$
$$ \Rightarrow {\rm Ka} = 100\,{\rm nM} $$

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Kaushik, P., Gorin, F. & Vali, S. Dynamics of tyrosine hydroxylase mediated regulation of dopamine synthesis. J Comput Neurosci 22, 147–160 (2007). https://doi.org/10.1007/s10827-006-0004-8

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