A New View into the Regulation of Purine Metabolism: The Purinosome

Pedley, Anthony M.; Benkovic, Stephen J.

doi:10.1016/j.tibs.2016.09.009

Cited by 429 publications

(406 citation statements)

References 89 publications

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“…Similar “metabolons”, defined as “supramolecular complexes of sequential metabolic enzymes and cellular structural elements” [119], have been observed in other systems, such as the tricarboxylic acid cycle [120], the purinosome [121], dhurrin biosynthesis [122], and steroid biosynthesis [123]. Identifying the functions of such metabolon organization remains an active area of research with multiple hypotheses.…”

Section: The Coq Biosynthetic Complexmentioning

confidence: 95%

Biochemistry of Mitochondrial Coenzyme Q Biosynthesis

Stefely

Pagliarini

2017

Trends in Biochemical Sciences

272

290

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Coenzyme Q (CoQ, ubiquinone) is a redox active lipid produced across all domains of life that functions in electron transport and oxidative phosphorylation and whose deficiency causes human diseases. Yet, CoQ biosynthesis has not been fully defined in any organism. Several proteins with unclear molecular functions facilitate CoQ biosynthesis through unknown means, and multiple steps in the pathway are catalyzed by currently unidentified enzymes. Here we highlight recent progress toward filling these knowledge gaps through both traditional biochemistry and cutting-edge “omics” approaches. To help fill the remaining gaps, we present questions framed by the recently discovered CoQ biosynthetic complex and by putative biophysical barriers. Mapping CoQ biosynthesis, metabolism, and transport pathways has great potential to enhance treatment of numerous human diseases.

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Section: The Coq Biosynthetic Complexmentioning

confidence: 95%

Biochemistry of Mitochondrial Coenzyme Q Biosynthesis

Stefely

Pagliarini

2017

Trends in Biochemical Sciences

272

290

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“…The cellular level of purines is maintained by coordinated actions of two pathways: the salvage pathway and the de novo biosynthesis pathway (for review, see Pedley and Benkovic 2017). The salvage pathway produces purines by recycling degraded bases in a single enzyme-catalyzed reaction (Murray 1971).…”

Section: Introductionmentioning

confidence: 99%

“…Under physiological conditions, the salvage pathway is responsible for controlling the basal cellular purine level. Under conditions with higher purine demands such as active cell growth, the de novo biosynthesis pathway plays a dominant role in increasing purine synthesis (Pedley and Benkovic 2017). It has been reported that the regulatory capacity of the de novo biosynthesis is greater than that of the salvage pathway (Yamaoka et al 1997).…”

Section: Introductionmentioning

confidence: 99%

Purine Biosynthesis Enzymes in Hippocampal Neurons

Williamson¹,

Petralia

Wang

et al. 2017

Neuromol Med

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Despite reports implicating disrupted purine metabolism in causing a wide spectrum of neurological defects, the mechanistic details of purine biosynthesis in neurons are largely unknown. As an initial step in filling that gap, we examined the expression and subcellular distribution of three purine biosynthesis enzymes (PFAS, PAICS and ATIC) in rat hippocampal neurons. Using immunoblotting and high-resolution light and electron microscopic analysis, we find that all three enzymes are broadly distributed in hippocampal neurons with pools of these enzymes associated with mitochondria. These findings suggest a potential link between purine metabolism and mitochondrial function in neurons and provide an impetus for further studies.

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“…94,95 Collectively, the formation of purinosomes, which indicates the upregulation of de novo purine biosynthesis, has significantly advanced our understanding of the regulatory mechanisms of de novo purine biosynthesis in human cells. 96–98 …”

Section: Nucleotide Biosynthesismentioning

confidence: 99%

Spatial Organization of Metabolic Enzyme Complexes in Cells

2017

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The organization of metabolic multienzyme complexes has been hypothesized to benefit metabolic processes and provide a coordinated way for the cell to regulate metabolism. Historically, their existence has been supported by various in vitro techniques. However, it is only recently that the existence of metabolic complexes inside living cells has come to light to corroborate this long-standing hypothesis. Indeed, subcellular compartmentalization of metabolic enzymes appears to be widespread and highly regulated. On the other hand, it is still challenging to demonstrate the functional significance of these enzyme complexes in the context of the cellular milieu. In this review, we discuss the current understanding of metabolic enzyme complexes by primarily focusing on central carbon metabolism and closely associated metabolic pathways in a variety of organisms, as well as their regulation and functional contributions to cells.

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A New View into the Regulation of Purine Metabolism: The Purinosome

Cited by 429 publications

References 89 publications

Biochemistry of Mitochondrial Coenzyme Q Biosynthesis

Biochemistry of Mitochondrial Coenzyme Q Biosynthesis

Purine Biosynthesis Enzymes in Hippocampal Neurons

Spatial Organization of Metabolic Enzyme Complexes in Cells

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