A Computational Systems Biology Approach to Decipher Significant Intricacies of Dihydrolipoamide Dehydrogenase Deficiency in Human
Abhishek Sengupta1, Sarika Saxena2, Gaurav Singh3, Priyanka Narad4, Ayushi Yadav5, Monendra Grover6
1Abhishek Sengupta, Amity Institute of Biotechnology, Amity University, Noida, India.
2Sarika Saxena, Amity Institute of Biotechnology, Amity University, Noida, India.
3Gaurav Singh , Amity Institute of Biotechnology, Amity University, Noida, India.
4Priyanka Narad, Amity Institute of Biotechnology, Amity University, Noida, India.
5Ayushi Yadav, Amity Institute of Biotechnology, Amity University, Noida, India.
6Monendra Grover, CABin, IASRI, ICAR, Pusa, New Delhi, India.
Manuscript received on March 02, 2014. | Revised Manuscript received on March 05, 2014. | Manuscript published on March 05, 2014. | PP: 166-170 | Volume-4 Issue-1, March 2014. | Retrieval Number: A2139034114 /2014©BEIESP
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© The Authors. Published By: Blue Eyes Intelligence Engineering and Sciences Publication (BEIESP). This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)
Abstract: The alpha-ketoglutarate dehydrogenase complex (KGDHC) is elemental in mitochondria, and its deficiency is associated with a number of neurological disorders like Alzheimer’s disease, Parkinson’s disease and Dihydrolipoamide dehydrogenase deficiency (DLDD). The molecular mechanisms underlying the age dependent loss of brain KGDHC activity remain incomprehensible. In order to disentangle this phenomenon, a kinetic model is developed representing correlations between three aspects namely the reduced AKGDHC activity; mitochondrial ATP generation and increased pyruvate concentration. The kinetic model centralizes on the mitochondrial-derived ATP production and is distributed into cytosol and mitochondria. The model revealed a decline in ATP production with lowered enzyme concentration. With the effect, the concentration of pyruvate was increased resulting in its excretion which is a characteristic feature of DLDD. In agreement with the previous literature the model simulations confirmed the decline in reaction fluxes and NADH level. The finding suggests that reduction of pyruvate is the rate limiting step of the TCAC which is supported by past bibliographic findings. Since ATP production is also affected by NADH production rate hence it can be safely assumed that decrease in NADH also causes Change in ATP production rate. Change in pyruvate concentration on changing the concentration of AKGDH also underpins the importance of the studied enzyme in DLDD. It is clearly indicated by simulations that AKGDH deficiency can cause increase in pyruvate concentration.
Keywords: Alpha-ketoglutarate dehydrogenase complex, Dihydrolipoamide dehydrogenase deficiency, kinetic model.