Biology Reference
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catalyzing sequential steps in a pathway. This type of analysis has been performed
both theoretically and experimentally, mainly in vitro (Ovadi et al.
2004
).
The supramolecular organization of metabolic enzymes and their interactions
with one another and with subcellular structures constitute the basis for cellular
microcompartmentation. Compartmentalized metabolic pathways or segment(s) of
these pathways can overcome diffusive barriers within the crowded intracellular
milieu since metabolism can successfully proceed and even be facilitated by metab-
olite channeling. In such channeling a direct transfer of intermediates from one
enzyme to an adjacent enzyme happens without the need for free aqueous-phase
diffusion. The enhanced probability of intermediates to be transferred from the
active site of one enzyme to the active site of the following enzyme in the pathway
requires stable or transient interactions between these enzymes. The structurally
organized assembly of enzymes associated physically in a non-dissociable, static
multienzyme complex would constitute a metabolon. Such metabolons, containing
enzymes of a part or a whole metabolic pathway, might therefore be fundamental
units in the control of these pathways. The formation of microcompartments is
particularly important at metabolite crossroads where the association of the enzymes
involved in one or other pathway determines the direction of the flux (Ovadi
1991
).
Thus, the supramolecular organization of the competing enzymes can control the
behavior of metabolic systems by providing distributed control.
The control of the energy metabolism (e.g., ATP synthesis) is tightly coupled
with several metabolic and signaling pathways [see, for example (Rostovtseva and
Bezrukov
2012
)], however, their exact relationship is unclear. Even less informa-
tion is available on the interconnections between the pathological ultrastructures
and energy (ATP) production at the molecular level.
Glucose is the major energy source in brain and is metabolized via glycolysis in
the cytoplasm coupled with oxidation via the Krebs cycle in the mitochondrion
synthesizing ATP as the key fuel for many metabolic and signaling pathways. The
polarization state of the mitochondrial membrane is related to the energy state of
the mitochondria which can be monitored in living cells by fluorescence micros-
copy using tetramethylrhodamine ethyl ester staining (Lehotzky et al.
2004
). For
example, K4 cells stably expressing EGFP-TPPP/p25 showed strikingly high fluo-
rescence intensity as compared with control neuroblastoma (SK-N-MC) cells
indicating that the expression of TPPP/p25 did not cause energy impairment but
actually enhanced the membrane potential (Fig.
7.5
). Consistent with this, the ATP
concentration was found to be higher in the extract of the K4 cells as compared with
that of control cells. Flux analysis of glucose metabolism in these cells revealed that
the enhanced ATP concentration resulted in increased energy state in K4 cells
(Orosz et al.
2004
). The cellular, biochemical, and computation results suggest that
the expression of the neomoonlighting TPPP/p25 protein in K4 cells is controlled
by an unknown mechanism that maintains the amount of this protein below toxic
levels (as revealed by the existence of a stable cell line); these results also suggest
that its expression is coupled with increased energy production.
Mitochondrial impairment has been reported in the case of Huntington's disease
(HD), a progressive neurodegenerative disorder caused by the insertion of a long
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