Allosteric regulation alters carrier domain translocation in pyruvate carboxylase

liu, yumeng; Budelier, Melissa M; Stine, Katelyn; Maurice, Martin St.

doi:10.1038/s41467-018-03814-8

Cited by 17 publications

(17 citation statements)

References 33 publications

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“…2B ). The large gene clearly encodes an enzyme including the biotin-binding domain and other regions diagnostic for carboxylases ( 36 ). The carboxylase is further identified as a guanidine-metabolizing enzyme by a specific active region demarcated in a previous study ( 35 ).…”

Section: Resultsmentioning

confidence: 99%

Filling in the Gaps in Metformin Biodegradation: a New Enzyme and a Metabolic Pathway for Guanylurea

Tassoulas

Robinson

Martinez‐Vaz

et al. 2021

Appl Environ Microbiol

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The widely prescribed pharmaceutical metformin and its main metabolite guanylurea are currently two of the most common contaminants in surface and wastewater. Guanylurea often accumulates and is poorly, if at all, biodegraded in wastewater treatment plants. This study describes Pseudomonas mendocina strain GU isolated from a municipal wastewater treatment plant using guanylurea as its sole nitrogen source. The genome was sequenced with 36-fold coverage and mined to identify guanylurea degradation genes. The gene encoding the enzyme initiating guanylurea metabolism was expressed, the enzyme purified and characterized. Guanylurea hydrolase, a newly described enzyme, was shown to transform guanylurea to one equivalent of ammonia and guanidine. Guanidine also supports growth as a sole nitrogen source. Cell yields from growth on limiting concentrations of guanylurea revealed that metabolism releases all four nitrogen atoms. Genes encoding complete metabolic transformation were identified bioinformatically, defining the pathway as follows: guanylurea to guanidine to carboxyguanidine to allophanate to ammonia and carbon dioxide. The first enzyme, guanylurea hydrolase, is a member of the isochorismatase-like hydrolase protein family that includes biuret hydrolase and triuret hydrolase. Although homologs, the three enzymes show distinct substrate specificities. Pairwise sequence comparisons and the use of sequence similarity networks allowed fine structure discrimination between the three homologous enzymes and provided insights into the evolutionary origins of guanylurea hydrolase. IMPORTANCE Metformin is a pharmaceutical most prescribed for type 2 diabetes and is now being examined for potential benefits to COVID-19 patients. People taking the drug pass it largely unchanged and it subsequently enters wastewater treatment plants. Metformin has been known to be metabolized to guanylurea. The levels of guanylurea often exceed that of metformin, leading to the former being considered a “dead end” metabolite. Metformin and guanylurea are water pollutants of emerging concern as they persist to reach non-target aquatic life and humans, the latter if it remains in treated water. The present study has identified a Pseudomonas mendocina strain that completely degrades guanylurea. The genome was sequenced and the genes involved in guanylurea metabolism were identified in three widely separated genomic regions. This knowledge advances the idea that guanylurea is not a dead end product and will allow for bioinformatic identification of the relevant genes in wastewater treatment plant microbiomes and other environments subjected to metagenomic sequencing.

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Section: Resultsmentioning

confidence: 99%

Filling in the Gaps in Metformin Biodegradation: a New Enzyme and a Metabolic Pathway for Guanylurea

Tassoulas

Robinson

Martinez‐Vaz

et al. 2021

Appl Environ Microbiol

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“…PC reaction does not produce NADH, CO 2 , and acetylCoA like the PDH enzyme reaction does; instead, it consumes one ATP and CO 2 to form OAA ( Figure 3 ). The PC enzyme reaction is favored in “over-energetic” situations like at Day4 ( Berg et al, 2002 ; Zhang et al, 2014 ; Liu et al, 2018 ). Based on the above, it is easier to understand why plasma pyruvate surprisingly continued to be also be statistically significantly downregulated in the placebo subgroup at Day 21 ( Figure 4A ).…”

Section: Resultsmentioning

confidence: 99%

Randomized Trial: D-Glyceric Acid Activates Mitochondrial Metabolism in 50–60-Year-Old Healthy Humans

et al. 2021

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Background: Based on earlier studies, natural metabolite D-glyceric acid (DGA) does not seem to play any role in whole-body metabolism. Nevertheless, one ethanol oxidation-related rat study with controversial results raised our interest. According to preparatory studies for the regulatory approval of DGA, some highly conserved mechanism seems to subtly activate the cellular energy metabolism. Therefore, the present 25-days double-blind human study with placebo control was initiated.Purpose: The main target in the present study with 27 healthy 50–60-year-old human volunteers was to find out whether an “acute” 4-days and a longer 21-days exogenous DGA regimen caused moderate activation of the mitochondrial energy metabolism. The simultaneous target was to find out whether a halved dose of DGA continued to be an effective regimen.Main Findings: The results revealed the following statistically significant findings: 1) plasma concentrations of metabolites related to aerobic energy production, especially lactate, were strongly reduced, 2) systemic inflammation was lowered both in 4- and 21-days, 3) mitochondria-related mRNA expressions in circulating immune cells were noticeably modulated at Day4, 4) cellular membrane integrity seemed to be sharply enhanced, and 5) cellular NADH/NAD+ -ratio was upregulated.Conclusion: Mitochondrial metabolism was clearly upregulated at the whole-body level in both 4- and 21 days. At the same time, the effect of DGA was very well tolerated. Based on received solid results, the DGA regimen may alleviate acute and chronic energy metabolic challenges in main organs like the liver, CNS, and skeletal muscles. Enhanced membrane integrity combined with lower systemic inflammation and activated metabolic flows by the DGA regimen may be beneficial especially for the aging population.

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“…The tetramer is arranged as a dimer of dimers, where the BCCP domains swings between any of the two BC and two CT domains of a dimer, allowing four different translocation routes to take place (Liu et al . 2018 ).…”

Section: The Different Enzymes Of the Ppo-nodementioning

confidence: 99%

The PEP-pyruvate-oxaloacetate node: variation at the heart of metabolism

Koendjbiharie

Kranenburg

Kengen

2020

FEMS Microbiology Reviews

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At the junction between the glycolysis and the tricarboxylic acid cycle—as well as various other metabolic pathways—lies the phosphoenolpyruvate (PEP)-pyruvate-oxaloacetate node (PPO-node). These three metabolites form the core of a network involving at least eleven different types of enzymes, each with numerous subtypes. Obviously, no single organism maintains each of these eleven enzymes; instead, different organisms possess different subsets in their PPO-node, which results in a remarkable degree of variation, despite connecting such deeply conserved metabolic pathways as the glycolysis and the tricarboxylic acid cycle. The PPO-node enzymes play a crucial role in cellular energetics, with most of them involved in (de)phosphorylation of nucleotide phosphates, while those responsible for malate conversion are important redox enzymes. Variations in PPO-node therefore reflect the different energetic niches that organisms can occupy. In this review, we give an overview of the biochemistry of these eleven PPO-node enzymes. We attempt to highlight the variation that exists, both in PPO-node compositions, as well as in the roles that the enzymes can have within those different settings, through various recent discoveries in both bacteria and archaea that reveal deviations from canonical functions.

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Allosteric regulation alters carrier domain translocation in pyruvate carboxylase

Cited by 17 publications

References 33 publications

Filling in the Gaps in Metformin Biodegradation: a New Enzyme and a Metabolic Pathway for Guanylurea

Filling in the Gaps in Metformin Biodegradation: a New Enzyme and a Metabolic Pathway for Guanylurea

Randomized Trial: D-Glyceric Acid Activates Mitochondrial Metabolism in 50–60-Year-Old Healthy Humans

The PEP-pyruvate-oxaloacetate node: variation at the heart of metabolism

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