Abstract
Nucleoside triphosphate (NTP)s, like ATP (adenosine 5'-triphosphate) and GTP (guanosine 5'-triphosphate), have long been considered sufficiently concentrated and diffusible to fuel all cellular ATPases (adenosine triphosphatases) and GTPases (guanosine triphosphatases) in an energetically healthy cell without becoming limiting for function. However, increasing evidence for the importance of local ATP and GTP pools, synthesised in close proximity to ATP- or GTP-consuming reactions, has fundamentally challenged our view of energy metabolism. It has become evident that cellular energy metabolism occurs in many specialised 'microcompartments', where energy in the form of NTPs is transferred preferentially from NTP-generating modules directly to NTP-consuming modules. Such energy channeling occurs when diffusion through the cytosol is limited, where these modules are physically close and, in particular, if the NTP-consuming reaction has a very high turnover, i.e. is very processive. Here, we summarise the evidence for these conclusions and describe new insights into the physiological importance and molecular mechanisms of energy channeling gained from recent studies. In particular, we describe the role of glycolytic enzymes for axonal vesicle transport and nucleoside diphosphate kinases for the functions of dynamins and dynamin-related GTPases.
Highlights
One hundred years ago, Michaelis and Menten described the enzyme kinetics of invertase, which today still forms the basis of a model describing the kinetic properties of many enzymes [republished in 1]
The main purpose of this review is to provide a clear and precise understanding of energy channeling, with an emphasis on recent examples of ATP channeling by glycolytic enzymes to ATPases and GTP channeling by nucleoside diphosphate kinases (NDPKs), in particular, to dynamin and dynamin-related GTPases
The finding of glycolytic enzymes in clathrin-coated vesicles and in early endosome fractions by proteomics analysis113 suggests that the latter may be the case114,115. Since mitochondria use their own ATP for their transport, not that produced by glycolysis, it would be intriguing to investigate whether a similar energy channeling exists between mitochondrial molecular motors and the ATP delivered by the voltage-dependent anion channel (VDAC) in the outer mitochondrial membrane (OMM)
Summary
Michaelis and Menten described the enzyme kinetics of invertase, which today still forms the basis of a model describing the kinetic properties of many enzymes [republished in 1]. This proximity allows preferred metabolite exchange (Figure 5b), where mtCK uses mainly mitochondrial ATP provided by ANT, together with cytosolic Cr, to generate ADP and PCr35,51 The degree of this direct channeling depends on the species, the tissue and the physiological state, but has been observed in many cell types (it is most pronounced in heart and skeletal muscle) and by means of several methods, including kinetic, radioisotopic and thermodynamic approaches. The finding of glycolytic enzymes in clathrin-coated vesicles and in early endosome fractions by proteomics analysis113 suggests that the latter may be the case114,115 Since mitochondria use their own ATP for their transport, not that produced by glycolysis, it would be intriguing to investigate whether a similar energy channeling exists between mitochondrial molecular motors and the ATP delivered by the VDAC in the OMM. NM23-H8 and NM23-H9, which are more phylogenetically divergent than NM23-H1 and NM23-H2, bind directly to microtubules231232
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