Research Activities

        Liebig's law of the minimum provides a fundamental basis for understanding biological regulation: how the biological regulations of some core life processes (e.g., metabolism, assimilation) at the levels of cells, molecules and ecosystems are influenced by the availability of "limiting resources", and conversely what are the biological determinants for the bioavailability of essential mineral elements that are often limiting in most ecosystems.

Liebig's law is originally developed in agricultural sciences, stating that growth is regulated not by total amount of resources, but by the scarcest resource i.e., limiting factor. This concept is eminently applied in agricultural practices and fertilizer industries to get eloquent control on plant or crop growth. However, a general principle can be formed based on this idea which underlies the process of regulation from molecules to ecosystems, allowing us to conceive existence of a limiting factor critical to biological regulation. Probing how this general principle works under different conditions and at different scales is fundamental to regulatory mechanisms. We have observed that a suite of regulatory mechanisms can emerge under the constraints of limiting factors.    

Working research problems

A kinetic mechanism underlying the robustness of the GDH ammonium assimilation system

  • Nitrogen assimilation and detoxification
Nitrogen is an essential mineral element for the biosynthesis of all amino acids and nucleotides and acts as limiting factor in most biosystems. However, nitrogen can also have toxic effects with its ammonium form generated as a by-product of amino acid metabolism. Hepatic cells play critical role for detoxifying ammonium and for maintaining ammonium homeostasis in systemic circulation (i.e., normal range 10-40 micro-mole per litre). But this same ammonium can also be an essential input in the synthesis of glutamate and glutamine-primary donors of amine and amide groups to most macromolecules. How the systemic ammonium homeostasis is maintained by balancing competing processes of detoxification and amino acids biosynthesis in hepatic cells remains elusive. I am targeting to unfold this mystery, examining how the N-assimilation maintains robust input-output ratios in response to large-extent variation of ammonium and alpha-keto glutarate substrate which are essentially adjusted according to the N-demand. I also address particularly glutamate dehydrogenase (GDH) enzyme dynamics. Over activity of GDH causes hyperinsulinism/hyperammonemia syndrome (HI/HA), resulting in recurrent hypoglycaemia in early infancy. This problem is tackled with systems biology and biophysical approaches combined with 'molecular dynamic simulation' tools and the available protein data bank (PDB) information.

Nitrate transporter NRT1.1 rigidity analysis for identifying allosteric communication pathways 

  • Nitrate signaling and uptake mechanisms in plants

Nitrate is most common bioavailable form of nitrogen taken up by the plants and microbes. To be assimilated, it has converted into ammonium by nitrate and nitrite reductase and then into amino acids by enzymes such as glutamate synthase. In addition to being an essential nutrient, nitrate also serves as signaling molecule. Out of several identified nitrate transporter proteins (i.e., NRT1 and NRT2 families), NRT1.1 has recently been shown to play the role of transceptor. This interesting molecule can sense nitrate availability and then adjust the primary nitrate response (PNR) by changing nitrate binding affinities. It has been demonstrated recently that NRT1.1 has biphasic toggle-switch type response to nitrate availabilities; at low nitrate, high affinity mode of transport is ON, whereas at high nitrate it changes to low-affinity mode. Here we are trying to examine how these biphasic responses are regulated and maintained in a wide-range of variation in nitrate availabilities. This question is addressed by means of signal transduction model integrated with Boolean gate. I am also seeking structural explanations by designing specific molecular dynamic (MD) simulation experiment. 

NRT1.1 Regulation

iScience (Cell Press) 2(2018): 41-50.The protomer A contains a high-affinity nitrate binding site, whereas the protomer B contains relatively a low-affinity binding site. Binding of nitrate ion triggers an allosteric communication between the binding site and the T101 site in protomer A that primes the T101 site for phosphorylation and responsible for activating the immediate downstream component of nitrate signaling CBL9.CIPK23 complex at low nitrate concentration. In contrast, such allosteric communication pathway is absent in protomer B. At low nitrate concentration, nitrate ion binds only at high-affinity site of protomer A and activates the CBL9.CIPK23 complex. At high-nitrate concentration, nitrate binds to both the sites of protomer A and protomer B and then continuously inhibits the activity of CBL9.CIPK23 complex along the increasing gradient of nitrate.

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