Anthony (Tony) Pedley

I am currently not accepting graduate students. Please consider many of the other great research laboratories in the Department.

Professional Appointment and Affiliation 

Associate Research Professor, Department of Chemistry

Office                                                                     

407 Wartik Laboratory                                         

Laboratory

412 Wartik Laboratory

Education

Postdoctoral Scholar, Chemistry, The Pennsylvania State University (2014-2020)

Ph.D., Medicinal Chemistry and Molecular Pharmacology, Purdue University (2013)

B.S., Chemistry, Grand Valley State University (2007)

Research Statement

The Pedley Research Group strives to understand how the structure, function, and fate of metabolic enzymes are regulated by molecular chaperones. We leverage a combination of chemical, biochemical, and genetic approaches to investigate the chaperone-associated mechanisms in response to changes in cellular biomass demands and nutrient availability. Insights gathered from these findings aim to identify new drug targets and inspire therapeutic strategies to treat MYC-driven cancers.

Active areas of exploration include: 

• Metabolon Organization and Dynamics: To maximize metabolite flux through a given pathway, metabolic enzymes cluster into transient and dynamic membrane-less organelles called metabolons. This project investigates the structural and functional features within a metabolon comprised of purine biosynthetic enzymes called the purinosome. We hypothesize that the metabolite flux through the purinosome is obtained by a unique enzyme composition whereas the slowest pathway enzymes is at a higher abundance than the faster enzymes. To test this, we leverage genome editing and super-resolution fluorescence microscopy to determine the relative stoichiometry between de novo purine biosynthetic enzymes. Given that two of the pathway enzymes are clients of Hsp90, we will investigate the influence that this class of molecular chaperones has on regulating the organization and biophysical properties of the purinosome. Together, these findings will provide insight into how these supramolecular assemblies are organized to maximize biomass and energy production. This project is in collaboration with Dr. Ruobo Zhou and Dr. Stephen Benkovic.  
• Metabolic Enzyme Structure and Function: We largely do not have an understanding for how molecular chaperones influence individual or classes of metabolic enzymes. Using our recent findings that purine metabolism is regulated by molecular chaperones, we are exploring how Hsp90 is acting on the structure and function of metabolic enzyme clients. We also are exploring whether conserved structural features across enzyme classes are possible signals for chaperone complex recruitment. Insights gathered from these studies will advance our understanding of how chaperones directly regulate metabolic enzymes and their respective pathways to alter metabolite production.   
• Nutrient- and Metabolite-induced Protein Degradation: One housekeeping function of the Hsp70 family of chaperones is the ability to recognize, sequester, and transport proteins to degradative machinery. Recently, it has been discovered that metabolic enzymes can be selectively targeted for degradation as a way to regulate a metabolic process. We are exploring how these metabolic enzymes are targeted to chaperones by investigating those biochemical features on both the metabolic enzyme client and the chaperone machinery. Findings from these studies will start to tease apart how chaperones can selectively recruit certain proteins and determine their fate in order to maintain protein homeostasis.

Representative Publications (reverse chronological order)

A current listing of all publications can be found here.

* denotes equal contribution

^ denotes undergraduate student researcher

1. ^Binder, MJ, Pedley, AM. The Roles of Molecular Chaperones in Regulating Cell Metabolism. FEBS Lett. 2023 Jul;597(13):1681-1701.

2. Pedley, AM, Pareek, V., Benkovic, SJ. The Purinosome: A Case Study for a Mammalian Metabolon. Annu Rev Biochem. 2022 Jun 21;91:89-106.

3. Pedley, AM, ^Boylan, JP, Chan, CY, Kennedy, EL, Kyoung, M., Benkovic, SJ. Purine biosynthetic enzymes assemble into liquid-like condensates dependent on the activity of chaperone protein HSP90. J Biol Chem. 2022 May;298(5): 101845.

4. *Doigneaux C., *Pedley AM, Mistry IN, Papayova M, Benkovic SJ, Tavassoli A. Hypoxia drives the assembly of the multienzyme purinosome complex. J Biol Chem. 2020 Jul 10;295(28):9551-9566.

5. *Chan CY, *Pedley AM, *Kim D, Xia C, Zhuang X, Benkovic SJ. Microtubule-directed transport of purine metabolons drives their cytosolic transit to mitochondria. Proc Natl Acad Sci USA. 2018 Dec 18;115(51):13009-13014.

6. Pedley AM, Karras GI, Zhang X, Lindquist S, Benkovic SJ. Role of HSP90 in the Regulation of de Novo Purine Biosynthesis. Biochemistry. 2018 Jun 12;57(23):3217-3221.

7. French JB, Jones SA, Deng H, Pedley AM, Kim D, Chan CY, Hu H, Pugh R, Zhao H, Zhang Y, Huang TJ, Fang Y, Zhuang X, Benkovic SJ. Spatial colocalization and functional link of purinosomes with mitochondria. Science. 2016 Feb 12;351(6274):733-737.