ATP Synthase: Structure, Function and Inhibition

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These data support the conclusion that ATP synthase is a major consumer of ATP during ischemia and/or metabolic inhibition, and they further demonstrated that the consumption of glycolytic ATP is used to maintain Δψ [87]. Therefore, other metabolic pathways must be activated (Box 1), including substrate-level phosphorylation (or anaerobic) and oxidative phosphorylation (or aerobic). The latter is critically dependent on the respiratory and cardiovascular systems, to ensure adequate oxygen delivery to contracting skeletal muscle, and on reducing equivalents from the metabolism of primarily carbohydrate and fat1. The anaerobic energy pathways have a much higher power (rate of ATP production) but a smaller capacity (total ATP produced) than the aerobic pathways2.

Thus, inhibition of the ATP synthase hydrolytic activity under these conditions conserves cellular ATP levels. The membrane potential prevents uncontrolled influx of ATP into the mitochondrial matrix via the electrogenic ATP/ADP translocator, thus limiting ATP hydrolysis. Furthermore, it is stated that during ischemia, the mitochondrial ATPase inhibitor protein (IF1) binds to and inhibits the mitochondrial ATPase, thereby conserving ATP [85,87,88,89]. IF1 can also contribute to the myocardial ischemic preconditioning, reducing the mitochondria damage during early reperfusion [90].

Citrate is then transformed into isocitrate by aconitase through the formation of cis-aconitate. This step is reversible and could lead to the formation of both citrate and isocitrate. Only the fast consumption of isocitrate by its dehydrogenase can force the reaction to the proper direction. Isocitrate dehydrogenase catalyzes the first irreversible oxidation leading to the decarboxylation of isocitrate, generating CO2 and α-ketoglutarate. The second carbon leaves the cycle in the following step, when the newly generated α-ketoglutarate is immediately decarboxylated by the α-ketoglutarate dehydrogenase complex in a reaction similar to the pyruvate decarboxylation.

  1. Since 1929, when it was discovered that ATP is a substrate for muscle contraction, the knowledge about this purine nucleotide has been greatly expanded.
  2. Subunits b, d, F6 and OSCP form the peripheral stalk, which connect both F1 and F0 and keep the stators (F1-αβ3 and F0a) from spinning along with the rotor (γδε and F0c).
  3. Thus, inhibition of the ATP synthase hydrolytic activity under these conditions conserves cellular ATP levels.
  4. Schematic representation of the ATP synthase modifications involved in the progression of human diseases.
  5. One of the key successes of our synthetic reductive metabolism includes improving the efficiency of the synthesis of more reduced compounds from input substrates of variable oxidation state.

An increase in adipose tissue lipolysis supports the progressive increase in plasma fatty acid uptake and oxidation21, but because lipolysis exceeds uptake and oxidation, plasma fatty acid levels increase. Inhibition of adipose tissue lipolysis increases the reliance on both muscle glycogen and IMTG but has little effect on muscle glucose uptake17. The importance of IMTG oxidation during exercise has been a matter of debate, and results in the literature may be influenced by differences in individuals’ training status, sex, fibre-type distribution and resting IMTG stores22.

The subsequent rush to biobank samples for molecular phenotyping has been unprecedented. Changes in metabolite and protein expression are now well-correlated with COVID-19 severity, and this approach may facilitate the identification of diagnostic and prognostic markers of disease, yield mechanistic insight and reveal potential therapeutic targets. However, whole blood or RBCs have been largely ignored in COVID-19 for proteomics or metabolomic profiling. A single study applied ‘omic approaches to isolated RBCs in COVID-19 (Thomas et al., 2020a), showing alterations in numerous metabolite classes, including free fatty acids, acylcarnitines and sphingolipids.


Succinate dehydrogenase (or complex II) is another entrance site for electrons into the respiratory chain. In this case, electrons derived from the oxidation of succinate are passed through FAD to ubiquinone. Once ubiquinone is reduced to ubiquinol, it is able to pass electrons to the third complex, ubiquinone/cytochrome c oxidoreductase.

What Is the Purpose of a Mitochondrial Membranes?

Moreover, these phosphorylated sites (which seem to be facing the “cytosolic” side of the IMM) can be dephosphorylated in a calcium-dependent manner by protein phosphatase 1 [38]. Another phosphorylation site was identified and published in the work of Lee et al. [39]. The authors described how complex IV inhibition could be mediated by another cAMP-dependent activity, this time, in subunit I. On the other hand, a PKA phosphorylation site was recently found on the matrix side of subunit IV. Four protein complexes and ATP synthase, all bound to the IMM, as well as two shuttles are the known players of one of the trickiest mechanisms resolved in biochemistry (Fig. 1). The first of these complexes is the NADH/ubiquinone oxidoreductase (complex I) which removes electrons from NADH (produced in the citric acid cycle) and passes them on to the first shuttle, ubiquinone, a liposoluble cofactor located within the phospholipid bilayer of the IMM.

Here, electrons are moved through several heme groups from the liposoluble shuttle ubiquinone to the water-soluble shuttle cytochrome c. Cytochrome c is a small protein (about 12.5 kDa), located in the intermembrane space (IMS), which can accommodate one electron in its heme group. Despite its water solubility, cytochrome c is usually bound to the external surface of the IMM due to the interaction with the cardiolipin [12]. This interaction (crucial in the determination of the cell fate) helps the shuttle to reach its electron acceptor, complex IV. Electrons from cytochrome c are accumulated in copper centers and passed to oxygen through heme groups. The first reaction of the citric acid cycle is the condensation of one acetyl-CoA and a molecule of citrate to generate oxaloacetate and is catalyzed by citrate synthase.

A process that regulates a transcriptional and translational response to endoplasmic reticulum protein folding stress. A quality control pathway that marks damaged mitochondria to promote their autophagy-mediated destruction. Ligand-regulated transcription factors that are activated by steroid hormones and other lipid-related molecules. One of the two atp generation cell types that build the alveolar epithelium, responsible for surfactant synthesis and secretion. Neurons located in the arcuate nucleus within the hypothalamus; they produce a polypeptide named pro-opiomelanocortin, whose proteolysis generates several peptide hormones (including α-melanocyte-stimulating hormone and adrenocorticotropic hormone).

A universal metabolite repair enzyme removes a strong inhibitor of the TCA cycle

To solve this problem and generate a more robust strain, we instead expressed IDH2 under its native promoter to obtain a fully functional TCA cycle in SynENG050, resulting in SynENG055. However, the titre of SynENG055 was reduced to 980 from 1,405 mg l–1 (strain SynENG050). We hypothesize that an overly strong TCA cycle competes for the carbon flow of fatty acid synthesis.

Metabolic and Functional Consequences of Anaerobic Red Blood Cell Storage

The structure of enzyme ATP synthase mimics an assembly of two motors with a shared common rotor shaft and stabilized by a peripheral stator stalk. The F1 part of ATP synthase is made up of 8 subunits, 3α, 3β, γ, δ and ε, where the γ, δ and ε subunits add up to the central stalk (or the rotor shaft) and an alternate arrangement of 3α and 3β form a hexameric ring with a central cavity. The γ subunit inserted in the central cavity protrudes out to meet ε which binds on its side and together they bind the F0. Bacterial F0 has the simplest subunit structure consisting a1, b2 and c10-14 subunits. Eukaryotic F0 has several subunits including d, F6 and the oligomycin sensitivity-conferring protein (OSCP). Subunits b, d, F6 and OSCP form the peripheral stalk, which connect both F1 and F0 and keep the stators (F1-αβ3 and F0a) from spinning along with the rotor (γδε and F0c).

This design should enable simple fine-tuning of NADH and NADPH supply in the cytoplasm of eukaryotes. Our results clearly demonstrate that the oxidative and non-oxidative PP pathways, and the activity of the trans-hydrogenase cycle, can support cell growth, thus providing a promising entry point for the construction of a synthetic energy system. Cellular function is the sum of a large number of coordinated chemical reactions, most clearly represented by catabolic processes where carbon and energy sources are converted to Gibbs free energy and the building blocks required for cellular proliferation1,2. In anabolic processes, building blocks are converted to macromolecules under the context of energy of consumption.