Passage 8: Glycolosis
“Understanding acid-base regulation is often reduced to pigeonholing clinical
states into categories of disorders based on arterial blood sampling. An earlier
ambition to quantitatively explain disorders by measuring the production and
elimination of acid has not become standard clinical practice. Seeking back to
classical physical chemistry we propose that in any compartment, the requirement
of electroneutrality leads to a strong relationship between charged moieties”.
Hypoxia inhibits the tricarboxylic acid (TCA) cycle and leaves glycolysis as the
primary metabolic pathway responsible for converting glucose into usable energy.
However, the mechanisms that compensate for this loss in energy production
due to TCA cycle inactivation remain poorly understood. Glycolysis enzymes
are typically diffuse and soluble in the cytoplasm under normoxic conditions. In
contrast, recent studies have revealed dynamic compartmentalization of glycolysis
enzymes in response to hypoxic stress in yeast, C. elegans and mammalian
cells. These messenger ribonucleoprotein (mRNP) structures, termed glycolytic
(G) bodies in yeast, lack membrane enclosure and display properties of phaseseparated biomolecular condensates. Disruption of condensate formation
correlates with defects such as impaired synaptic function in C. elegans neurons
and decreased glucose flux in yeast. Concentrating glycolysis enzymes into
condensates may lead to their functioning as ‘metabolons’ that enhance rates of
glucose utilization for increased energy production.
Glycolysis is a core energy-producing pathway in cells; it converts glucose to two
net ATPs and pyruvates, which can then be utilized by the mitochondria to generate
an additional 34 ATPs through oxidative phosphorylation in the tricarboxylic acid
(TCA) cycle. Glycolysis and its related pathways are shown in Figure 1.
Hypoxic stress precludes the function of the highly efficient oxidative
phosphorylation pathway and limits energy production to glycolysis. Despite
substantial work on cellular adaptations to hypoxia, how cells compensate for this
decreased energy efficiency is not fully understood.
In cancer cell lines, both glycolytic and gluconeogenic enzymes localize to puncta
called glucosomes. Furthermore, many enzymes are shared between the opposing
gluconeogenesis and glycolysis pathways, with allosteric regulation of human
phosphofructokinase (PFKL, glycolysis) and fructose-1,6-bisphosphatase (FBPase,
gluconeogenesis) largely governing which pathway predominates. Both of these
enzymes localize to glucosomes, in addition to phosphoenolpyruvate carboxykinase
(PEPCK) and PYK; therefore, allosteric regulation of these enzymes within granules
may influence flux through the opposing pathways.
Source: Fuller & Kim (2021), Compartmentalization and metabolic regulation of
glycolysis.
If there is a rare mutation that prevents chromosome 21 from duplicating
properly which causes the gene that codes phosphofructokinase undergoes a
nonsense mutation, which of the following would be a likely result?
A) One metabolic pathway will be downregulated
B) One metabolic pathway will be affected
C) More than one metabolic pathway will be affected
D) More than one metabolic pathway will be upregulated
Correct answer: C. First, it’s important to understand the implications
of the question stem. If the gene that codes for the PFK enzyme undergoes
a nonsense mutation, this means that the DNA has a mutation that causes a
premature STOP for the translated mRNA. This would create a nonfunctional
enzyme, thus reducing the amount of functional PFK enzyme in the cell. Since
the passage discusses that phosphofructokinase is one of the enzymes that are
involved in both “gluconeogenesis and glycolysis pathways,” any alteration of
this enzyme would affect more than one metabolic pathway. Since the nonsense
mutation would decrease the amount of active PFK in the system, this would act
as a bottleneck to both pathways since they require PFK to function. Therefore, we
can’t say that this would upregulate more than two pathways. In fact, it will likely
downregulate both pathways. Therefore, option choice C is the right answer.
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