Abstract
While a plethora of genetic techniques have been developed over the past century, modifying specific sequences of the fruit fly genome has been a difficult, if not impossible task. clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9 truly redefined molecular genetics and provided new tools to model human diseases in Drosophila melanogaster. This is particularly true for genes whose protein sequences are highly conserved. Phosphoribosyl pyrophosphate synthetase (PRPS) is a rate-limiting enzyme in nucleotide metabolism whose missense mutations are found in several neurological disorders, including Arts syndrome. In addition, PRPS is deregulated in cancer, particularly those that become resistant to cancer therapy. Notably, Drosophila PRPS shares about 90% protein sequence identity with its human orthologs, making it an ideal gene to study via CRISPR/Cas9. In this review, we will summarize recent findings on PRPS mutations in human diseases including cancer and on the molecular mechanisms by which PRPS activity is regulated. We will also discuss potential applications of Drosophila CRISPR/Cas9 to model PRPS-dependent disorders and other metabolic diseases that are associated with nucleotide metabolism.
Highlights
Inborn mutations causing metabolic disorders, in purine and pyrimidine genes, often result in a variety of nervous system disorders [1,2,3,4]
Among the three human orthologs, missense mutations of PRPS1 are found in a number of rare neurological disorders such as Arts syndrome
Studies have discovered that PRPS1 and PRPS2 are mutated in therapy-resistant relapsed acute lymphoblastic leukemia (ALL) cancer patients
Summary
Inborn mutations causing metabolic disorders, in purine and pyrimidine genes, often result in a variety of nervous system disorders [1,2,3,4]. Like mice, could provide important insights into mechanisms of pathogenesis and treatment options, one has to consider the cost-benefit analysis of various approaches For these reasons, Drosophila melanogaster is an excellent system to model rare diseases affecting the nervous system. The suitability of such an approach would depend on the degree of sequence and functional conservation between the human and Drosophila orthologs One such metabolic gene is phosphoribosyl pyrophosphate synthetase (PRPS), the rate-limiting enzyme in nucleotide metabolism. PRPS is the rate-limiting enzyme in nucleotide biosynthesis that is responsible for the transfer of the β-γ diphosphate of ATP to the C1 hydroxyl of ribose-5-phosphate (R5P), which is a compound produced by the pentose phosphate pathway [11] This produces phosphoribosyl pyrophosphate (PRPP), a common precursor of the five-carbon sugar unit of all nucleotides. PRPS is the rate-limiting enzyme in nucleotide metabolism as it produces PRPP, a critical molecule for nucleotide biogenesis
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