Purine Nucleotides Metabolism and Signaling in Huntington’s Disease: Search for a Target for Novel Therapies

Huntington’s disease (HD) is a multi-system disorder that is caused by expanded CAG repeats within the exon-1 of the huntingtin (HTT) gene that translate to the polyglutamine stretch in the HTT protein. HTT interacts with the proteins involved in gene transcription, endocytosis, and metabolism. HTT may also directly or indirectly affect purine metabolism and signaling. We aimed to review existing data and discuss the modulation of the purinergic system as a new therapeutic target in HD. Impaired intracellular nucleotide metabolism in the HD affected system (CNS, skeletal muscle and heart) may lead to extracellular accumulation of purine metabolites, its unusual catabolism, and modulation of purinergic signaling. The mechanisms of observed changes might be different in affected systems. Based on collected findings, compounds leading to purine and ATP pool reconstruction as well as purinergic receptor activity modulators, i.e., P2X7 receptor antagonists, may be applied for HD treatment.

Differing thermal sensitivities of physiological processes alter ATP allocation

Changes in environmental temperature impact rate processes at all levels of biological organization. Yet, the thermal sensitivity of specific physiological processes that impact allocation of the ATP pool within a species is less well understood. In this study of developmental stages of the Pacific oyster, Crassostrea gigas, thermal sensitivities were measured for growth, survivorship, protein synthesis, respiration, and transport of amino acids and ions. At warmer temperatures, larvae grew faster but suffered increased mortality. An analysis of temperature sensitivity (Q10 values) revealed that protein synthesis, the major ATP-consuming process in larvae of C. gigas, is more sensitive to temperature change (Q10 value of 2.9±0.18) than is metabolic rate (Q10 of 2.0±0.15). Ion transport by Na+/K+-ATPase measured in vivo has a Q10 value of 2.1±0.09. The corresponding value for glycine transport is 2.4±0.23. Differing thermal responses for protein synthesis and respiration result in a disproportional increase in the allocation of available ATP to protein synthesis with rising temperature. A bioenergetic model is presented illustrating how changes in growth and temperature impact allocation of the ATP pool. Over an environmentally relevant temperature range for this species, the proportion of the ATP pool allocated to protein synthesis increases from 35% to 65%. The greater energy demand to support protein synthesis with increasing temperature will compromise energy availability to support other essential physiological processes. Defining the tradeoffs of ATP demand will provide insights into understanding the adaptive capacity of organisms to respond to various scenarios of environmental change.

Photosynthetic cyclic electron transport provides ATP for homeostasis during trap closure in Dionaea muscipula

Background and Aims The processes connected with prey capture and the early consumption of prey by carnivorous Dionaea muscipula require high amounts of energy. The aim of the present study was to identify processes involved in flytrap energy provision and ATP homeostasis under these conditions. Methods We determined photosynthetic CO2 uptake and chlorophyll fluorescence as well as the dynamics of ATP contents in the snap traps upon closure with and without prey. Key Results The results indicate that upon prey capture, a transient switch from linear to cyclic electron transport mediates a support of ATP homeostasis. Beyond 4 h after prey capture, prey resources contribute to the traps’ ATP pool and, 24 h after prey capture, export of prey-derived resources to other plant organs may become preferential and causes a decline in ATP contents. Conclusions Apparently, the energy demand of the flytrap for prey digestion and nutrient mining builds on both internal and prey-derived resources.

Manipulation of the ATP pool as a tool for metabolic engineering

Cofactor engineering has been long identified as a valuable tool for metabolic engineering. Besides interventions targeting the pools of redox cofactors, many studies addressed the adenosine pools of microorganisms. In this mini-review, we discuss interventions that manipulate the availability of ATP with a special focus on ATP wasting strategies. We discuss the importance to fine-tune the ATP yield along a production pathway to balance process performance parameters like product yield and volumetric productivity.

Genetics and Physiology of Acetate Metabolism by the Pta-Ack Pathway of Streptococcus mutans

ABSTRACTIn the dental caries pathogenStreptococcus mutans, phosphotransacetylase (Pta) catalyzes the conversion of acetyl coenzyme A (acetyl-CoA) to acetyl phosphate (AcP), which can be converted to acetate by acetate kinase (Ack), with the concomitant generation of ATP. A ΔackAmutant displayed enhanced accumulation of AcP under aerobic conditions, whereas little or no AcP was observed in the Δptaor ΔptaΔackAmutant. The Δptaand ΔptaΔackAmutants also had diminished ATP pools compared to the size of the ATP pool for the parental or ΔackAstrain. Surprisingly, when exposed to oxidative stress, the ΔptaΔackAstrain appeared to regain the capacity to produce AcP, with a concurrent increase in the size of the ATP pool compared to that for the parental strain. The ΔackAand ΔptaΔackAmutants exhibited enhanced (p)ppGpp accumulation, whereas the strain lacking Pta produced less (p)ppGpp than the wild-type strain. The ΔackAand ΔptaΔackAmutants displayed global changes in gene expression, as assessed by microarrays. All strains lacking Pta, which had defects in AcP production under aerobic conditions, were impaired in their abilities to form biofilms when glucose was the growth carbohydrate. Collectively, these data demonstrate the complex regulation of the Pta-Ack pathway and critical roles for these enzymes in processes that appear to be essential for the persistence and pathogenesis ofS. mutans.