# Equipment Supplement: Mechanisms that govern assembly and function of higher order protein structures of purine metabolic enzymes

> **NIH NIH R35** · UNIVERSITY OF MINNESOTA · 2020 · $80,000

## Abstract

Supramolecular complexes ranging from processing bodies to focal adhesion sites are increasingly found to be
common elements of cellular structure and function. The purinosome is a recently discovered supramolecular
protein complex that regulates, both temporally and spatially, the metabolism of purine nucleotides. Because of
the fundamental significance of purine biosynthesis, the novelty of this type of spatiotemporal regulation, and the
importance of this pathway as a drug target, there is a critical need to elucidate the mechanisms that dictate
purinosome structure and function. Little is known about how such structures are formed, regulated or trafficked,
nor is there a clear understanding of how these systems control metabolic flux. The long term goal of my
research program is to understand how transient, supramolecular protein complexes regulate cellular
metabolism. The overall objectives for the proposed funding period are to 1) define the structural features and
extrinsic factors that control purinosome function, 2) quantify the kinetic and metabolic advantages that this
protein structure provides, and 3) identify functional associations that purinosomes make with other cellular
structures. The central hypothesis underlying these studies is that purinosome proteins undergo structural
changes, in response to external signals, which drive the assembly process. In addition, we hypothesize that
purinosomes are actively trafficked along microtubules, in response to specific signals, towards certain cellular
structures such as the nucleus or plasma membrane. This level of control enables cells to specifically upregulate
the production of purines and metabolic intermediates at a specific cellular locus. The rationale for the proposed
research is that the purinosome is an important regulatory mechanism for the biosynthesis of purines, the purine
biosynthetic pathway is critical to life, and is a clinically validated drug target. Thus, a better understanding of the
purinosome will provide a clearer picture of overall nucleotide metabolism with potential to translate into more
selective and potent antimetabolite drugs. The approach that we are taking is innovative, in the applicant’s
opinion, because it departs from the status quo by integrating a suite of interdisciplinary tools to probe the system
at multiple time and length scales. This will enable us to directly link molecular determinants of function with the
corresponding biological outputs at physiologically relevant time and length scales. The outcome of these studies
will be the elucidation of key, physiologically relevant and potentially druggable, interactions central to
purinosome function, a mechanistic model that is likely generalizable to similar protein structures, and a
quantitative determination of in vitro enzymatic and in vivo metabolic effects of this structure. The proposed
research is significant, because it will provide sorely needed details of the structure, function and m...

## Key facts

- **NIH application ID:** 10135484
- **Project number:** 3R35GM124898-04S1
- **Recipient organization:** UNIVERSITY OF MINNESOTA
- **Principal Investigator:** Jarrod B French
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $80,000
- **Award type:** 3
- **Project period:** 2017-09-10 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10135484

## Citation

> US National Institutes of Health, RePORTER application 10135484, Equipment Supplement: Mechanisms that govern assembly and function of higher order protein structures of purine metabolic enzymes (3R35GM124898-04S1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10135484. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*