Human de novo purine biosynthesis

Pareek, Vidhi; Pedley, Anthony M.; Benkovic, Stephen J.

doi:10.1080/10409238.2020.1832438

Cited by 82 publications

(77 citation statements)

References 111 publications

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“…Thus, both the glycine and formate resulting from mitochondrial C1 metabolism are incorporated into the purine ring. To facilitate an efficient flux of pathway intermediates, de novo purine biosynthetic enzymes are assembled into a “purinosome” [ 73 ], which mediates passage of the key intermediates, including the THF cofactors between the sequential steps from PRPP to AMP and GMP. Purinosomes are reported to co-localize with mitochondria to further maximize the metabolic efficiency of purine biosynthesis [ 73 ].…”

Section: Folate Homeostasis Folate Transport and One-carbon Metabolismmentioning

confidence: 99%

Folate Transport and One-Carbon Metabolism in Targeted Therapies of Epithelial Ovarian Cancer

Wallace-Povirk

Hou

Nayeen

et al. 2021

Cancers

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New therapies are urgently needed for epithelial ovarian cancer (EOC), the most lethal gynecologic malignancy. To identify new approaches for targeting EOC, metabolic vulnerabilities must be discovered and strategies for the selective delivery of therapeutic agents must be established. Folate receptor (FR) α and the proton-coupled folate transporter (PCFT) are expressed in the majority of EOCs. FRβ is expressed on tumor-associated macrophages, a major infiltrating immune population in EOC. One-carbon (C1) metabolism is partitioned between the cytosol and mitochondria and is important for the synthesis of nucleotides, amino acids, glutathione, and other critical metabolites. Novel inhibitors are being developed with the potential for therapeutic targeting of tumors via FRs and the PCFT, as well as for inhibiting C1 metabolism. In this review, we summarize these exciting new developments in targeted therapies for both tumors and the tumor microenvironment in EOC.

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Section: Folate Homeostasis Folate Transport and One-carbon Metabolismmentioning

confidence: 99%

Folate Transport and One-Carbon Metabolism in Targeted Therapies of Epithelial Ovarian Cancer

Wallace-Povirk

Hou

Nayeen

et al. 2021

Cancers

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“…In humans, the de novo purine biosynthetic pathway requires six enzymes and ten successive steps to convert PRPP into IMP [56]. The 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/inosine monophosphate (IMP) cyclohydrolase (ATIC) enzyme is a cytosolic bifunctional enzyme that catalyzes the final two steps of the pathway.…”

Section: Biological Rolementioning

confidence: 99%

Current Status of the Use of Multifunctional Enzymes as Anti-Cancer Drug Targets

Teixeira

Sousa

2021

Pharmaceutics

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Fighting cancer is one of the major challenges of the 21st century. Among recently proposed treatments, molecular-targeted therapies are attracting particular attention. The potential targets of such therapies include a group of enzymes that possess the capability to catalyze at least two different reactions, so-called multifunctional enzymes. The features of such enzymes can be used to good advantage in the development of potent selective inhibitors. This review discusses the potential of multifunctional enzymes as anti-cancer drug targets along with the current status of research into four enzymes which by their inhibition have already demonstrated promising anti-cancer effects in vivo, in vitro, or both. These are PFK-2/FBPase-2 (involved in glucose homeostasis), ATIC (involved in purine biosynthesis), LTA4H (involved in the inflammation process) and Jmjd6 (involved in histone and non-histone posttranslational modifications). Currently, only LTA4H and PFK-2/FBPase-2 have inhibitors in active clinical development. However, there are several studies proposing potential inhibitors targeting these four enzymes that, when used alone or in association with other drugs, may provide new alternatives for preventing cancer cell growth and proliferation and increasing the life expectancy of patients.

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“…It has recently been suggested that phosphorylation of these enzymes is mainly driven by the PI3K, AKT, and mTOR kinases and serves as a key mechanism to enhance individual enzyme activity and the overall de novo purine synthesis flux, for example, during the G1 phase of the cell cycle (Liu et al, 2019). These PTMs are also considered to be pivotal for controlling assembly into a multienzyme complex, the so-called purinosome, that channels pathway intermediates to increase purine synthesis when the salvage mechanism is insufficient (Pareek et al, 2021). It has been proposed that in evolution, assembly into purinosomes is a more recent development that benefits compartmentalized eukaryotes, for example by microtubule-dependent migration of the complex into proximity to mitochondria where the necessary cofactors and one-carbon molecules are generated (Pareek et al, 2021 S3.…”

Section: Smis Coordinate Different Purine Pathways and Metazoan Ptms Optimize De Novo Synthesismentioning

confidence: 99%

“…These PTMs are also considered to be pivotal for controlling assembly into a multienzyme complex, the so-called purinosome, that channels pathway intermediates to increase purine synthesis when the salvage mechanism is insufficient (Pareek et al, 2021). It has been proposed that in evolution, assembly into purinosomes is a more recent development that benefits compartmentalized eukaryotes, for example by microtubule-dependent migration of the complex into proximity to mitochondria where the necessary cofactors and one-carbon molecules are generated (Pareek et al, 2021 S3.…”

Section: Smis Coordinate Different Purine Pathways and Metazoan Ptms Optimize De Novo Synthesismentioning

confidence: 99%

Conservation of metabolic regulation by phosphorylation and non-covalent small-molecule interactions

2021

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Human de novo purine biosynthesis

Cited by 82 publications

References 111 publications

Folate Transport and One-Carbon Metabolism in Targeted Therapies of Epithelial Ovarian Cancer

Folate Transport and One-Carbon Metabolism in Targeted Therapies of Epithelial Ovarian Cancer

Current Status of the Use of Multifunctional Enzymes as Anti-Cancer Drug Targets

Conservation of metabolic regulation by phosphorylation and non-covalent small-molecule interactions

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