Caloric excess or restriction mediated modulation of metabolic enzyme acetylation-proposed effects on cardiac growth and function

Caloric excess has been postulated to disrupt cardiac function via (i) the generation of toxic intermediates, (ii) via protein glycosylation and (iii) through the generation of reactive oxygen species. It is now increasingly being recognized that the nutrient intermediates themselves may modulate metabolic pathways through the post-translational modifications of metabolic enzymes. In light of the high energy demand of the heart, these nutrient mediated modulations in metabolic pathway functioning may play an important role in cardiac function and in the capacity of the heart to adapt to biomechanical stressors. In this review the role of protein acetylation and deacetylation in the control of metabolic programs is explored. Although not extensively investigated directly in the heart, the emerging data support that these nutrient mediated post-translational regulatory events (i) modulate cardiac metabolic pathways, (ii) integrate nutrient flux mediated post-translational effects with cardiac function and (iii) may be important in the development of cardiac pathology. Areas of investigation that need to be explored are highlighted. This article is part of a Special Issue entitled: Mitochondria and Cardioprotection.     

The role of bundle sheath extensions and life form in stomatal responses to leaf water status

Bundle sheath extensions (BSEs) are key features of leaf structure with currently little-understood functions. To test the hypothesis that BSEs reduce the hydraulic resistance from the bundle sheath to the epidermis (r(be)) and thereby accelerate hydropassive stomatal movements, we compared stomatal responses with reduced humidity and leaf excision among 20 species with heterobaric or homobaric leaves and herbaceous or woody life forms. We hypothesized that low r(be) due to the presence of BSEs would increase the rate of stomatal opening (V) during transient wrong-way responses, but more so during wrong-way responses to excision (V(e)) than humidity (V(h)), thus increasing the ratio of V(e) to V(h). We predicted the same trends for herbaceous relative to woody species given greater hydraulic resistance in woody species. We found that V(e), V(h), and their ratio were 2.3 to 4.4 times greater in heterobaric than homobaric leaves and 2.0 to 3.1 times greater in herbaceous than woody species. To assess possible causes for these differences, we simulated these experiments in a dynamic compartment/resistance model, which predicted larger V(e) and V(e)/V(h) in leaves with smaller r(be). These results support the hypothesis that BSEs reduce r(be). Comparison of our data and simulations suggested that r(be) is approximately 4 to 16 times larger in homobaric than heterobaric leaves. Our study provides new evidence that variations in the distribution of hydraulic resistance within the leaf and plant are central to understanding dynamic stomatal responses to water status and their ecological correlates and that BSEs play several key roles in the functional ecology of heterobaric leaves.     

Flavobacterium johnsoniae as a model organism for characterizing biopolymer utilization in oligotrophic freshwater environments

Biopolymers are important substrates for heterotrophic bacteria in oligotrophic freshwater environments, but information on bacterial growth kinetics with biopolymers is scarce. The objective of this study was to characterize bacterial biopolymer utilization in these environments by assessing the growth kinetics of Flavobacterium johnsoniae strain A3, which is specialized in utilizing biopolymers at μg liter⁻¹ levels. Growth of strain A3 with amylopectin, xyloglucan, gelatin, maltose, or fructose at 0 to 200 μg C liter⁻¹ in tap water followed Monod or Teissier kinetics, whereas growth with laminarin followed Teissier kinetics. Classification of the specific affinity of strain A3 for the tested substrates resulted in the following affinity order: laminarin (7.9 × 10⁻² liter·μg⁻¹ of C·h⁻¹) ≫ maltose > amylopectin ≈ gelatin ≈ xyloglucan > fructose (0.69 × 10⁻² liter·μg⁻¹ of C·h⁻¹). No specific affinity could be determined for proline, but it appeared to be high. Extracellular degradation controlled growth with amylopectin, xyloglucan, or gelatin but not with laminarin, which could explain the higher affinity for laminarin. The main degradation products were oligosaccharides or oligopeptides, because only some individual monosaccharides and amino acids promoted growth. A higher yield and a lower ATP cell⁻¹ level was achieved at ≤10 μg C liter⁻¹ than at >10 μg C liter⁻¹ with every substrate except gelatin. The high specific affinities of strain A3 for different biopolymers confirm that some representatives of the classes Cytophagia-Flavobacteria are highly adapted to growth with these compounds at μg liter⁻¹ levels and support the hypothesis that Cytophagia-Flavobacteria play an important role in biopolymer degradation in (ultra)oligotrophic freshwater environments.     

Emerging characterization of the role of SIRT3-mediated mitochondrial protein deacetylation in the heart

Studies to quantify the protein acetylome show that lysine-residue acetylation rivals phosphorylation in prevalence as a posttranslational modification. Interesting, this posttranslational modification is modified by nutrient flux and by redox stress and targets the vast majority of metabolic pathway proteins in the mitochondria. Furthermore, the mitochondrial deacetylase enzyme SIRT3 appears to be regulated by exercise in skeletal muscle and in response to pressure overload in the heart. The alteration of protein lysine residues by acetylation and the enzymes controlling deacetylation are beginning to be explored as important regulatory events in the control of mitochondrial function and homeostasis. This review focuses on the mitochondrial targets of SIRT3 that are functionally implicated in heart biology and pathology and on the direct cardiac consequences of the genetic manipulation of SIRT3. As therapeutic modulators of other SIRT isoforms have been identified, the longer-term objective of our understanding of this biology would be to identify SIRT3 modulators as putative cardiac therapeutic agents.     

Caloric excess or restriction mediated modulation of metabolic enzyme acetylation—proposed effects on cardiac growth and function

Caloric excess has been postulated to disrupt cardiac function via (i) the generation of toxic intermediates, (ii) via protein glycosylation and (iii) through the generation of reactive oxygen species. It is now increasingly being recognized that the nutrient intermediates themselves may modulate metabolic pathways through the post-translational modifications of metabolic enzymes. In light of the high energy demand of the heart, these nutrient mediated modulations in metabolic pathway functioning may play an important role in cardiac function and in the capacity of the heart to adapt to biomechanical stressors. In this review the role of protein acetylation and deacetylation in the control of metabolic programs is explored. Although not extensively investigated directly in the heart, the emerging data support that these nutrient mediated post-translational regulatory events (i) modulate cardiac metabolic pathways, (ii) integrate nutrient flux mediated post-translational effects with cardiac function and (iii) may be important in the development of cardiac pathology. Areas of investigation that need to be explored are highlighted. This article is part of a Special Issue entitled: Mitochondria and Cardioprotection.     

Stomatal development: cross talk puts mouths in place

Stomata are crucial for the productivity and survival of land plants. Until recently, little was known about the events and molecular pathways required for stomatal development. Emerging data indicate that cell-cell signaling conveys spatial information about cell identity and location. Such information might pattern stomata by orienting the plane of asymmetric division and might control stomatal number by regulating division frequency. This pathway also provides an accessible model system for studying post-apical meristem stem cells that generate specific tissues.     

1H-Pyrazolo[3,4-b]pyridine inhibitors of cyclin-dependent kinases: highly potent 2,6-Difluorophenacyl analogues

Structure-activity studies of 1H-pyrazolo[3,4-b]pyridine 1 have resulted in the discovery of potent CDK1/CDK2 selective inhibitor 21h, BMS-265246 (CDK1/cycB IC(50)=6 nM, CDK2/cycE IC(50)=9 nM). The 2,6-difluorophenyl substitution was critical for potent inhibitory activity. A solid state structure of 21j, a close di-fluoro analogue, bound to CDK2 shows the inhibitor resides coincident with the ATP purine binding site and forms important H-bonds with Leu83 on the protein backbone.     

Regulation of autophagy and mitophagy by nutrient availability and acetylation

Normal cellular function is dependent on a number of highly regulated homeostatic mechanisms, which act in concert to maintain conditions suitable for life. During periods of nutritional deficit, cells initiate a number of recycling programs which break down complex intracellular structures, thus allowing them to utilize the energy stored within. These recycling systems, broadly named “autophagy”, enable the cell to maintain the flow of nutritional substrates until they can be replenished from external sources. Recent research has shown that a number of regulatory components of the autophagy program are controlled by lysine acetylation. Lysine acetylation is a reversible post-translational modification that can alter the activity of enzymes in a number of cellular compartments. Strikingly, the main substrate for this modification is a product of cellular energy metabolism: acetyl-CoA. This suggests a direct and intricate link between fuel metabolites and the systems which regulate nutritional homeostasis. In this review, we examine how acetylation regulates the systems that control cellular autophagy, and how global protein acetylation status may act as a trigger for recycling of cellular components in a nutrient-dependent fashion. In particular, we focus on how acetylation may control the degradation and turnover of mitochondria, the major source of fuel-derived acetyl-CoA.