Research Rotation Project

Analysis of the Disease Pathway by Dynamics of the Adenylosuccinate lyase (ADSL)

Banu Ozkan
Home Department - Physics
Areas of Study - Protein Folding and Dynamics
Office - PSF 350
Phone - 4809652890
E-mail - Banu.Ozkan@asu.edu
Designation - Theoretical

Adenylosuccinate lyase (ADSL) is an enzyme involved in the de novo purine biosynthesis required for several important biological functions. Occasionally disturbances within the enzyme occur, causing a disorder known as ADSL deficiency. ADSL deficiency is characterized by psychomotor retardation, muscle wasting, hypotonia, and behavioral changes such as autistic features, aggressiveness and self-mutilation. One of these conditions, autism spectrum disorder (ASD) alone affects more than 1.5 million Americans. About 40% of ADSL deficiency patients have features of ASD. The incidence of ASD is increasing for reasons that are not clear, and is expected to create a serious public health problem with increasing social and economic burdens. Hence it is important to understand the complex biology behind ASD. Experimental studies have shown that the enzyme defect is manifested by an increased concentration of metabolites of ADSL substrates in urine, CSF and plasma. Some of the mutations found in patients are lethal where others result in mild phenotypes. The lack of knowledge sequence-structure-function relationship challenges have hindered our understanding of how exactly ADSL deficiency causes the disease and demands new approaches. Several questions remain unanswered: a) is it the loss of ADSL enzymatic activity (perhaps in specific developmental stages or in particular tissues) that causes the disease and if so what structural features cause the loss of activity? b) is it the formation of toxic intermediates in the pathway as a result of ADSL deficiency that lead to the disorder? Additional possibilities that have not been considered exist as well. Another novel possibility is that mutated forms of ADSL may inhibit formation of the recently discovered multienzyme complex necessary for purine synthesis. We will employ theoretical modeling to answer the effects of mutation on structure and functions. Thus, a detailed study of enzyme structure-function relationship will be carried out for different (associated with different degree of severity of the disease. We will use recently developed elastic network method called specific Gaussian Network Model to study the changes in function upon mutation. Elastic Network Models have been effectively used to functionally related fluctuation dynamics of proteins. In Elastic Network Models, the folded structure of a protein is assumed as a three-dimensional elastic network subject to uniform, single-parameter harmonic potential between all residue pairs, bonded or non-bonded, located within a certain cutoff distance. In this model, high frequency modes give kinetically important residues (i.e residues important for folding and binding) whereas low frequency modes give the global motions of the proteins which are known to be important for the protein function. This project will be in collaboration with an experimentalist group where they will perform enzymatic activity analysis, substrate binding measurements and biochemical characterization of different mutants of ADSL.