The “great” controlling nucleotide coenzymes

Veech, Richard L.; King, Michael; Pawlosky, Robert J.; Kashiwaya, Yoshiaki; Bradshaw, Patrick C.; Curtis, William M.

doi:10.1002/iub.1997

Cited by 40 publications

(54 citation statements)

References 85 publications

(108 reference statements)

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“…The dianionic phosphate group (DPG) is ubiquitous in biochemical processes. It is the terminal end of various DNA and RNA nucleotides and several coenzymes including adenosine and guanosine di‐ and triphosphates (ADP, ATP, GDP, GTP), thiamine diphosphate (ThDP), pyridoxal phosphate (PLP) and nicotinamide adenine dinucleotide phosphate (NADPH) . Numerous proteins in their lifetimes become phosphorylated/dephosphorylated at Tyr, Ser, Thr, and His side‐chains .…”

Section: Introductionmentioning

confidence: 99%

Calibration of the dianionic phosphate group: Validation on the recognition site of the homodimeric enzyme phosphoglucose isomerase

et al. 2020

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We calibrate and validate the parameters necessary to represent the dianionic phosphate group (DPG) in molecular mechanics. DPG is an essential fragment of signaling biological molecules and protein-binding ligands. It is a constitutive fragment of biosensors, which bind to the dimer interface of phosphoglucose isomerase (PGI), an intracellular enzyme involved in sugar metabolism, as well as an extracellular protein known as autocrine motility factor (AMF) closely related to metastasis formation. Our long-term objective is to design DPG-based biosensors with enhanced affinities for AMF/PGI cancer biomarker in blood. Molecular dynamics with polarizable potentials could be used toward this aim. This requires to first evaluate the accuracy of such potentials upon representing the interactions of DPG with its PGI ligands and tightly bound water molecules. Such evaluations are done by comparisons with high-level ab initio quantum chemistry (QC) calculations. We focus on the Sum of Interactions Between Fragments Ab initio computed (SIBFA) polarizable molecular mechanics procedure. We present first the results of the DPG calibration. This is followed by comparisons between ΔE(SIBFA) and ΔE(QC) regarding bi-molecular complexes of DPG with the main-chain and side-chain PGI residues, which bind to it in the recognition site. We then consider DPG complexes with an increasing number of PGI residues. The largest QC complexes encompass the entirety of the recognition site, with six structural water molecules totaling up to 211 atoms. A persistent and satisfactory agreement could be shown between ΔE(SIBFA) and ΔE(QC). These validations constitute an essential first step toward large-scale molecular dynamics simulations of DPG-based biosensors bound at the PGI dimer interface. WWW.C-CHEM.ORG J. Comput. Chem. 2020, 41, 839-854 WWW.CHEMISTRYVIEWS.COM 105 to 225 , at fixed θ angle of 270 . Points 29-35 (E): 30 variations of the O-P-O 2 -H angle, from 0 to 180 , at fixed θ angle of 225 . Points 36-42 (F): 30 variations of the O─P─O 2 ─H angle, from 0 to 180 , at fixed θ angle of 255 . Points 43-49 (G): 30 variations of the O─P─O 3 ─H angle, from 0 to 180 , at fixed θ angle of 225 . Points 50-56 (H): 30 variations of the O─P─O 3 ─H angle, from 0 to 180 , at fixed θ angle of 255 . [Color figure can be viewed at wileyonlinelibrary.com] WWW.C-CHEM.ORG

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Section: Introductionmentioning

confidence: 99%

Calibration of the dianionic phosphate group: Validation on the recognition site of the homodimeric enzyme phosphoglucose isomerase

et al. 2020

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“…In contrast to the elevated expression of the shuttle components at later stages, at the 2C stage, by far the most important dehydrogenase that is expected to control the redox balance of the embryo is LDHB. Conversion of lactate to pyruvate by LDHB leads to high NADH levels (Veech et al, 2019). LDHB activity in the early embryo is 10-fold greater than in any somatic tissue, and its measured activity far exceeds that of all other metabolic enzymes (Brinster, 1965;Epstein et al, 1969).…”

Section: Mechanisms Of Metabolic Plasticitymentioning

confidence: 99%

“…Pyruvate deprivation will cause a further rise in the NADH:NAD + (Veech et al, 2019). This is borne out by the fact that Asp levels are 13-fold lower and glycerol-3P is 10-fold higher in morulae when they are cultured in a pyruvate-free medium (with normal lactate and glucose) compared with one in which lactate is depleted (with normal pyruvate and glucose) ( Figure 4A, B).…”

Section: Mechanisms Of Metabolic Plasticitymentioning

confidence: 99%

Metabolic Plasticity drives Development during Mammalian Embryogenesis

Sharpley

Chi

Banerjee

2020

Preprint

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SummaryPreimplantation mouse embryos interact minimally with their environment, and development is largely driven by metabolic processes. During the earliest cleavage stages, metabolism is rigid, with maternal deposits enforcing a redox state that facilitates zygotic genome activation. As maternal control falls, metabolic shuttles are activated, increasing glycolysis and equilibrating the TCA cycle. The resulting flexibility of nutrient utilization and metabolic plasticity facilitates unidirectional developmental progression such that later stage embryos proceed to form blastocysts without any exogenously added nutrients. We explore the mechanisms that govern this choreographed sequence that balances the deposition, degradation, synthesis and function of metabolic enzymes with redox control, bioenergetics and biosynthesis. Cancer cells follow a distinct metabolic strategy from that of the preimplantation embryo. However, important shared features emerge under reductive stress. We conclude that metabolic plasticity drives normal development while stress conditions mimic hallmark events in Cancer Metabolism.

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“…Restricted KDs and calorie restriction are antiinvasive, antiangiogenic, anti-inflammatory, and capable of killing tumor cells through a pro-apoptotic mechanism (181)(182)(183)(184)(185)(186)(187)(188). Metabolism of the major circulating ketone body, D-betahydroxybutyrate, reduces reactive oxygen species production through the mitochondrial Co-enzyme Q couple in normal cells, while simultaneously elevating oxidative stress in tumor cells (34, [189][190][191]. Implementation of KMT prior to any surgical procedure could also benefit patients (152).…”

Section: Ketogenic Metabolic Therapymentioning

confidence: 99%

Consideration of Ketogenic Metabolic Therapy as a Complementary or Alternative Approach for Managing Breast Cancer

et al. 2020

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Breast cancer remains as a significant cause of morbidity and mortality in women. Ultrastructural and biochemical evidence from breast biopsy tissue and cancer cells shows mitochondrial abnormalities that are incompatible with energy production through oxidative phosphorylation (OxPhos). Consequently, breast cancer, like most cancers, will become more reliant on substrate level phosphorylation (fermentation) than on oxidative phosphorylation (OxPhos) for growth consistent with the mitochondrial metabolic theory of cancer. Glucose and glutamine are the prime fermentable fuels that underlie therapy resistance and drive breast cancer growth through substrate level phosphorylation (SLP) in both the cytoplasm (Warburg effect) and the mitochondria (Q-effect), respectively. Emerging evidence indicates that ketogenic metabolic therapy (KMT) can reduce glucose availability to tumor cells while simultaneously elevating ketone bodies, a non-fermentable metabolic fuel. It is suggested that KMT would be most effective when used together with glutamine targeting. Information is reviewed for suggesting how KMT could reduce systemic inflammation and target tumor cells without causing damage to normal cells. Implementation of KMT in the clinic could improve progression free and overall survival for patients with breast cancer.

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The “great” controlling nucleotide coenzymes

Cited by 40 publications

References 85 publications

Calibration of the dianionic phosphate group: Validation on the recognition site of the homodimeric enzyme phosphoglucose isomerase

Calibration of the dianionic phosphate group: Validation on the recognition site of the homodimeric enzyme phosphoglucose isomerase

Metabolic Plasticity drives Development during Mammalian Embryogenesis

Consideration of Ketogenic Metabolic Therapy as a Complementary or Alternative Approach for Managing Breast Cancer

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