Biochemistry I (Week 14)
Metabolism
Cells carry out chemical reactions in organized steps called pathways, such as glycolysis. In these pathways, the product of one reaction
becomes the starting material for the next. Pathways are grouped into two main types: catabolic pathways, which break down large
molecules like proteins, fats, and carbohydrates into smaller ones such as carbon dioxide, water, and ammonia, and anabolic pathways,
which build complex molecules like glycogen from smaller components such as glucose. These pathways often connect to form a network
of chemical reactions that work together efficiently. The term metabolism refers to all the chemical changes happening in a cell, tissue, or
the entire body, while metabolites are the intermediate products of these chemical reactions. The main focus is on the metabolic pathways
that create and break down carbohydrates, fats, and proteins.
Metabolism is easier to understand when we break it down into smaller
pathways. Each pathway is made up of several enzymes, and each enzyme
plays a key role in speeding up or controlling the process. This image shows a
metabolic map of the main pathways involved in energy metabolism.
This “big picture” helps us see how different pathways are connected, how
molecules move through them and what happens if something blocks a
pathway (like a drug or a missing enzyme due to a genetic disorder).
Catabolic and Anabolic reactions
Catabolic reactions break down energy-rich molecules to produce ATP, the cell's main energy source. Catabolic pathways are usually
oxidative, meaning they need oxidized coenzymes like NAD⁺ to work. Catabolism also breaks down food or stored molecules into simpler
parts, which the body can use to build more complex molecules.
Catabolic reactions occur in three main stages. First, large molecules in food are broken down into smaller building blocks: proteins are
degraded into amino acids, carbohydrates (polysaccharides) into simple sugars (monosaccharides), and fats into fatty acids and glycerol.
Next, these smaller components are further broken down into simple molecules like acetyl coenzyme A (acetyl-CoA), generating a small
amount of ATP. Finally, acetyl-CoA enters the TCA (Krebs) cycle, where it is oxidized, producing a large amount of ATP through oxidative
phosphorylation as electrons from NADH and FADH₂ are transferred to oxygen.
Process of building complex
molecules from simpler ones.
This process requires energy,
typically from ATP.
Breaking down large molecules into
smaller ones to release energy, usually
in the form of ATP.
Anabolism is the opposite of catabolism. It is a process where a few simple molecules, like amino acids, are used to build a wide variety of
complex molecules, like proteins. Anabolic reactions require energy (endergonic), which comes from breaking down ATP into ADP and
inorganic phosphate (Pi). Unlike catabolism, which releases energy (exergonic), anabolism uses energy and involves chemical reductions.
These reductions often rely on NADPH as the electron donor.
Metabolic Map
A metabolic map is a visual diagram showing how different chemical
reactions and pathways in a cell are connected. It highlights how
molecules are broken down (catabolism) to release energy and how
they are built up (anabolism) to create essential compounds. The
map typically includes key pathways like glycolysis, the citric acid
cycle (TCA cycle), and oxidative phosphorylation, showing how
energy and building blocks are produced and used.
The tricarboxylic acid (TCA) cycle, also known as the citric acid or
Krebs cycle, is a key part of metabolism. It is where the breakdown of
carbohydrates, amino acids, and fatty acids meets. Their carbon
atoms are turned into carbon dioxide (CO2), and this process helps
produce most of the ATP in animals, including humans. The cycle
happens in the mitochondria, close to the electron transport chain
(ETC), which uses oxygen (O2) to help oxidize the molecules produced
in the cycle (NADH and FADH2).
Some reactions, like the breakdown of certain amino acids, add
intermediates to the cycle (called anaplerotic reactions). The cycle
also provides important molecules for building other substances,
such as glucose, amino acids, and heme. Because of this, the TCA
cycle is not a closed system but an open one, with compounds
constantly entering and leaving as needed.
Metabolic Map
The major way all these metabolic pathways (glucose, amino acids,
fatty acids, ketone bodies) are linked to the TCA cycle is that they all
contribute to providing acetyl-CoA (AcoA), which is the main starting
component for the cycle.
In addition to acetyl-CoA, some of these pathways also produce
intermediates that can directly enter the TCA cycle. For example,
succinyl-CoA can be produced from catabolism of valine, isoleucine,
and odd-chain fatty acids. Other intermediates that directly enter the
TCA cycle include oxaloacetate from transamination or deamination
of aspartate, α-ketoglutarate from transamination or deamination of
glutamate, fumarate from catabolism of phenylalanine and tyrosine,
and malate, which can be synthesized from pyruvate via pyruvate
carboxylation (an anaplerotic reaction).
Pyruvate metabolism
Pyruvate, the end product of glycolysis, can be metabolized through four distinct pathways depending on cellular conditions and energy
demands:
1. Pyruvate is transaminated to alanine in a reaction catalyzed by the
enzyme alanine aminotransferase (ALT). This reaction involves the transfer
of an amino group from glutamate to pyruvate, producing alanine and αketoglutarate. This reaction is a key step in the alanine (Cahill) cycle, where
alanine serves as a carrier of nitrogen and carbon between muscle and
liver.
During intense activity or fasting, muscle generates pyruvate from glycolysis and combines it with nitrogen from glutamate to form
alanine, preventing nitrogen buildup and conserving energy. Alanine is transported to the liver, where it is converted back to pyruvate by
ALT, transferring the amino group to α-ketoglutarate to form glutamate. Glutamate releases ammonia, which enters the urea cycle for
excretion. The pyruvate in the liver is used for gluconeogenesis to produce glucose, which is released into the bloodstream and taken up
by muscles as fuel, completing the cycle. Alanine cycle is crucial for maintaining energy balance and nitrogen homeostasis.
Pyruvate metabolism
2. Pyruvate can be carboxylated to oxaloacetate by the enzyme pyruvate
carboxylase in the mitochondria. This reaction requires ATP and biotin as
cofactors and is crucial for gluconeogenesis and replenishing intermediates
in the TCA cycle (anaplerosis).
3. In aerobic conditions, pyruvate is oxidatively decarboxylated to acetylCoA by pyruvate dehydrogenase complex (PDH). This reaction produces
CO₂ and NADH and is an essential step for entry into the TCA cycle and
fatty acid synthesis.
4. Under anaerobic conditions or during high-intensity exercise, pyruvate
is reduced to lactate by the enzyme lactate dehydrogenase (LDH). This
process regenerates NAD⁺ from NADH, which is necessary for continued
glycolysis. Lactate is transported to the liver, where it is converted back to
pyruvate and used for gluconeogenesis as part of the Cori cycle.
Lactate buildup can lead to lactic acidosis. However, the Cori cycle helps
prevent this by transporting lactate to the liver, where it can be converted
back into pyruvate and used for gluconeogenesis, reducing the risk of
acidosis.
Pyruvate Dehydrogenase complex
The major source of acetyl CoA for the TCA cycle is the oxidative decarboxylation of pyruvate by the multienzyme pyruvate dehydrogenase
complex (PDH complex, or PDHC). However, the PDHC is not a component of the TCA cycle. Pyruvate, the end product of glycolysis, is
transported from the cytosol into the mitochondrial matrix by the pyruvate mitochondrial carrier (MPC) of the inner mitochondrial
membrane. In the matrix, the PDHC converts pyruvate to acetyl CoA.
The pyruvate dehydrogenase complex (PDHC) is made up of three main enzymes: pyruvate
decarboxylase (E1 or PDH), dihydrolipoyl transacetylase (E2), and dihydrolipoyl dehydrogenase (E3).
Each enzyme handles a specific step in converting pyruvate to acetyl-CoA, and their close arrangement
ensures the reactions occur in the correct order without releasing intermediates.
The PDHC also includes two regulatory enzymes: PDH kinase, which inactivates the complex, and PDH
phosphatase, which activates it.
The pyruvate dehydrogenase complex (PDHC) requires five coenzymes to carry out its reactions:
thiamine pyrophosphate (TPP) for E1 (pyruvate decarboxylase), lipoic acid and CoA (active form of
vitamin B5) for E2 (dihydrolipoyl transacetylase), and FAD and NAD⁺ for E3 (dihydrolipoyl
dehydrogenase). TPP, lipoic acid, and FAD are tightly bound to the enzymes and function as prosthetic
groups.
Pyruvate Dehydrogenase complex
The different elements of the pyruvate dehydrogenase complex work together to convert pyruvate into acetyl-CoA. The first step involves
the E1 subunit, which decarboxylates pyruvate, releasing CO₂ and creating a 2-carbon intermediate called the hydroxyethyl group. Then E1
adds this intermediate to thiamine pyrophosphate (active form of vitamin B1), forming hydroxyethyl-TPP.
Next, the E2 subunit transfers the hydroxyethyl group from TPP to lipoamide (the active form of lipoic acid), forming hydroxyethyllipoamide.
The hydroxyethyl group is then oxidized by the E3 enzyme,
using NAD⁺ and FAD⁺ as electron acceptors. During this
oxidation process, two electrons are removed, converting the
hydroxyethyl group into acetyl group. This process involves
the reduction of lipoamide (the disulfide bond in lipoamide is
reduced to form dihydrolipoamide) while the hydroxyethyl
group is oxidized to form acetyl-dihydrolipoamide.
After oxidation step, the acetyl group is transferred from
dihydrolipoamide to the coenzyme A (CoA), catalyzed by E2,
resulting in the formation of acetyl-CoA, which enters the
citric acid cycle (TCA cycle) for energy production.
Finally, the reduced dihydrolipoamide is regenerated back to
its active form (lipoamide) by E3, which involves the
oxidation of dihydrolipoamide back to lipoamide, using NAD⁺
as an electron acceptor. NADH and H⁺ are produced during
this step.
PDHC cofactors
TPP is the active form of thiamine (vitamin B1). TPP is created by the
phosphorylation of thiamine into thiamine monophosphate (TMP), and
then TMP is further phosphorylated to form thiamine pyrophosphate (TPP).
The enzyme which catalyzes these reaction steps is known as thiamine
pyrophosphokinase, which uses ATP as the phosphate donor.
FAD+ (flavin adenine dinucleotide) is synthesized from riboflavin (vitamin B2). During the
synthesis process, riboflavin is first converted into FMN (flavin mononucleotide) by the action
of riboflavin kinase. In the next step, the enzyme FMN adenylyltransferase adds AMP (from
ATP) to FMN, creating FAD.
FAD+ can accept 2 electrons and 2 protons (H+) to generate FADH2. This molecule serves as an
electron carrier, which can donate electrons to the electron transport chain (ETC), ultimately
contributing to the production of ATP.
Lipoic acid is attached to a lysine residue on the E2 subunit via an amide bond, catalyzed by lipoate protein
ligase (LplA).
PDHC cofactors
NAD⁺ (nicotinamide adenine dinucleotide) is synthesized from niacin (vitamin B3), also known as
nicotinic acid. In addition to dietary intake, niacin can also be synthesized from tryptophan.
Niacin is converted to nicotinamide mononucleotide (NMN) by the enzyme known as nicotinic acid
phosphoribosyltransferase (NAPRT), using PRPP (phosphoribosyl pyrophosphate) as a donor. NMN
is then converted to NAD⁺ by the enzyme NMN adenylyltransferase, which adds an AMP (from ATP)
to NMN.
NAD⁺ (nicotinamide adenine dinucleotide) can accept 2 electrons and 1 proton (H⁺) to generate
NADH. This molecule serves as an electron carrier, which can donate electrons to the electron
transport chain (ETC), ultimately contributing to the production of ATP.
CoA (Coenzyme A) is synthesized from pantothenic acid (vitamin B₅), along with cysteine and ATP, through a multi-step enzymatic pathway.
just like a FAD and NAD, CoA is also nucleotide coenzyme (is synthesised by the adding the vitamin to nucleotide).
CoA primarily functions to facilitate the transfer and activation of acetyl (CH₃-C=O) or other acyl (R-C=O) groups in enzymatic reactions,
playing a central role in metabolic pathways such as the citric acid cycle, fatty acid metabolism, and biosynthetic processes.
PDHC regulation
The PDH kinase is activated by high levels of ATP, acetyl-CoA, and NADH, which signals that the cell has enough energy, so it shuts down
the PDHC. Pyruvate, on the other hand, inhibits PDH kinase, allowing E1 to stay active when pyruvate levels are high.
Calcium (Ca²⁺) activates PDH phosphatase, which increases E1 activity. This is important in skeletal muscle, where Ca²⁺ release during
muscle contraction stimulates the PDHC to produce more energy. Although the kinase and phosphatase regulation are key, PDHC activity
can also be inhibited by high levels of its products, NADH and acetyl-CoA.
When the NAD⁺/NADH ratio is increased, it indicates that the cell has a low
amount of NADH available for the electron transport chain (ETC) and thus
reduced capacity for ATP synthesis. Additionally, high levels of ADP suggest
low ATP availability, signaling increased demand for energy, while elevated
cytoplasmic calcium (Ca²⁺) levels in skeletal muscle cells indicate muscle
contraction, a state requiring high energy production. Together, these signals
reflect a high cellular energy demand, and as a result, the PDHC must be
activated to produce more acetyl-CoA for the TCA cycle, ultimately
increasing ATP synthesis via the ETC.
In contrast, when the NAD⁺/NADH ratio is decreased, it indicates a high
NADH level, reflecting sufficient electron donors for the ETC and ATP
synthesis. Additionally, high levels of ATP indicate that the cell already has
sufficient energy, while elevated acetyl-CoA levels suggest an abundant
supply of a key TCA cycle intermediate. These signals indicate that the cell
has an adequate energy supply and does not require additional ATP
synthesis, leading to the inhibition of PDHC activity.
PDHC deficiency
A deficiency in the α subunits of the E1 component of the pyruvate dehydrogenase complex (PDHC) is a rare cause of congenital lactic
acidosis. This deficiency reduces the ability to convert pyruvate into acetyl-CoA, causing pyruvate to be turned into lactate instead, leading
to lactic acid buildup. This is particularly harmful to the brain, which relies on the TCA cycle for energy and is sensitive to acidosis.
Symptoms can vary and may include brain damage, muscle stiffness, and early death in infants.
In addition to lactic acidosis, the situation is worsened because the reduction of acetyl-CoA formation inhibits TCA cycle activity, leading to
decreased energy production. AcoA is also an essential activator of pyruvate carboxylase (PC), and without it, this enzyme cannot be
activated, resulting in reduced formation of oxaloacetate. This further diminishes TCA cycle activity and also impairs gluconeogenesis,
contributing to a further reduction in energy production, particularly in tissues like the brain.
On the other hand, similar to lactic acid, the formation of alanine from accumulated pyruvate is also increased, leading to an elevation of
alanine levels, which typically starts in infancy.
Currently there is no proven cure, but limiting carbohydrates in the diet, increasing the intake of ketogenic nutrients (e.g. high-fat content
or high lysine and leucine) as alternative sources for acetyl-CoA formation, and taking thiamine (a key cofactor for PDHC) may help
alleviate symptoms in some patients.
Alcoholics usually have thiamine deficiency for several reasons, including poor diet, impaired absorption due to damage to the
gastrointestinal (GI) tract, liver damage (which reduces the liver's ability to store and activate thiamine into its active form, TPP), and
increased excretion of thiamine through the urine (as alcohol increases thiamine excretion by the kidneys).
This must be considered in clinical practice because administering glucose to alcoholics with thiamine deficiency can lead to severe lactic
acidosis, a potentially fatal condition. Without sufficient thiamine, the PDHC cannot function properly, causing pyruvate to accumulate and
be converted into lactate (lactic acid).
Arsenic poisoning mainly affects enzymes that need lipoic acid as a coenzyme, including PDH, α-ketoglutarate dehydrogenase, and
branched-chain α-keto acid dehydrogenase. Arsenite (the toxic form of arsenic) binds to the thiol (−SH) groups of lipoic acid, preventing it
from working properly. This leads to the buildup of pyruvate and lactate, similar to PDHC deficiency. The brain is especially affected,
causing neurological problems and even death. Patient may exhibit a garlic-like odor on their breath, which is caused by the oxidation of
arsenic to arsenous oxide, responsible for the characteristic smell. Nonspecific symptoms of arsenic poisoning include vomiting, diarrhea.
TCA cycle
TCA cycle is a central pathway in cellular metabolism that generates high-energy
molecules, such as NADH, FADH₂ (which are used in the electron transport chain
for ATP synthesis) and GTP. TCA cycle takes place in the mitochondrial matrix.
AcoA donates two carbon atoms to the TCA cycle. During the cycle, these carbons
are removed as CO₂ (So, for each round of the TCA cycle, there is no net gain or
loss of intermediates). As a result, the carbons from acetyl-CoA cannot be directly
used for the synthesis of oxaloacetate (OAA), a precursor for gluconeogenesis.
This means acetyl-CoA cannot be directly utilized for gluconeogenesis. However,
acetyl-CoA plays a crucial role in triggering gluconeogenesis.
The first step of the TCA cycle is the synthesis of citrate, a 6-carbon molecule,
through the irreversible condensation of the 4-carbon molecule oxaloacetate
(OAA) with the 2-carbon molecule acetyl-CoA (AcoA). This reaction is catalyzed by
the enzyme citrate synthase, which is inhibited by high levels of ATP and citrate.
When ATP is high, it indicates that the cell already has sufficient energy, so the
TCA cycle is downregulated to prevent the production of more ATP.
Citrate itself is an important indicator of the cell’s energy status. High levels of
citrate inhibit glycolysis (as no additional energy is needed) and activate fatty acid
synthesis (to store excess energy).
TCA cycle
At the next step of the TCA cycle, aconitase catalyzes the conversion of citrate to
cis-aconitate, and then the conversion of cis-aconitate to isocitrate (an isomer of
citrate). This step is reversible.
Aconitase can be inhibited by a rat poison called fluoroacetate. When this poison
enters the body, it is converted into fluoroacetyl-CoA, which then reacts with
oxaloacetate (OAA) to form fluorocitrate. Fluorocitrate is a potent inhibitor of
aconitase, blocking its activity in the TCA cycle.
In the next step of the TCA cycle, the six-carbon molecule isocitrate undergoes
oxidative decarboxylation to form the five-carbon molecule α-ketoglutarate.
During this reaction, a carbon atom is removed from isocitrate in the form of CO₂.
This irreversible step is catalyzed by isocitrate dehydrogenase, an enzyme that
utilizes NAD⁺ to facilitate the oxidative step, resulting in the production of NADH.
The NADH generated can then enter the electron transport chain (ETC) to drive
ATP synthesis.
This reaction represents one of the key rate-limiting steps of the TCA cycle.
Isocitrate dehydrogenase is inhibited by high levels of ATP and NADH, indicating
that the cell is in high-energy state and doesn’t require additional ATP production.
Conversely, When ADP levels are high, it means the cell is low on energy. This
activates the enzyme, helping it produce more ATP, the cell's main energy source.
Additionally, elevated cytoplasmic Ca²⁺ levels, particularly in skeletal muscle cells
during contraction (a state demanding high energy production) also activate
isocitrate dehydrogenase.
TCA cycle
The next irreversible step in the TCA cycle involves the synthesis of the fourcarbon molecule succinyl-CoA through the oxidative decarboxylation of the fivecarbon molecule α-ketoglutarate. This reaction is catalyzed by the α-ketoglutarate
dehydrogenase complex, which consists of multiple copies of three different
enzymes and operates in a manner similar to the PDHC. The reaction requires five
coenzymes: TPP, lipoic acid, FAD, NAD⁺, and CoA, each of which plays a specific
role in the reaction mechanism.
During this reaction, one carbon atom from α-ketoglutarate is released in the
form of CO₂, and the remaining four-carbon structure is attached to CoA to form
succinyl-CoA. This process also generates a second molecule of NADH, which can
enter ETC to drive ATP synthesis.
This step can be inhibited by succinyl-CoA through feedback inhibition, as well as
by elevated levels of NADH. In skeletal muscle cells, increased Ca²⁺ levels in the
cytoplasm can activate the enzyme's activity.
TCA cycle
The next reversible step in the TCA cycle is catalyzed by succinate thiokinase (also
known as succinyl-CoA synthetase), which breaks the high-energy thioester bond
of succinyl-CoA. This process removes CoA from succinyl-CoA, resulting in the
production of succinate. The reaction is coupled with the phosphorylation of GDP
to form GTP, which can be used for energy. It should be mentioned that GTP and
ATP can be converted into each other through a reaction catalyzed by nucleoside
diphosphate kinase (GTP + ADP ⇄ GDP + ATP). succinyl-CoA is is very important
substrate for the synthesis of heme molecule and hemoglobin.
Additionally, succinyl-CoA can be derived from propionyl-CoA, a product of the
metabolism of fatty acids with an odd number of carbon atoms and certain amino
acids. Succinyl-CoA can also be converted into pyruvate for gluconeogenesis.
In the next step, succinate is oxidized to form fumarate. This reaction is catalyzed
by succinate dehydrogenase (also known as Complex II in ETC), which uses FAD as
the electron acceptor. During this process, FAD is reduced to FADH2, which can be
used in the electron transport chain for ATP synthesis.
Succinate dehydrogenase is the only enzyme in the TCA cycle located in the inner
mitochondrial membrane. Because of this, it also functions as Complex II in the
ETC, serving as the enzyme for both the TCA cycle and the ETC.
Fumarate can also be synthesized in the urea cycle, during purine synthesis
(specifically in IMP synthesis), and during the breakdown of amino acids such as
tyrosine and phenylalanine. As a result, all of these reactions can contribute
fumarate to the TCA cycle.
TCA cycle
In the next step, fumarate is hydrated to malate in a freely reversible reaction
catalyzed by the enzyme fumarase.
In the final reversible step of the TCA cycle, malate is oxidized to oxaloacetate
(OAA) by the enzyme malate dehydrogenase. This enzyme uses NAD⁺ as the
electron acceptor, producing the third and final NADH of the cycle, which can be
ETC for ATP synthesis. Malate can be used in the malate-aspartate shuttle.
OAA can also be produced from the amino acid aspartic acid through a process
called transamination, or it can be generated from pyruvate by the enzyme
pyruvate carboxylase.
Each turn of the TCA cycle generates 3 NADH, 1 FADH₂, and 1 GTP. Each NADH
produces 2.5 ATP when oxidized by the electron transport chain (ETC), and each
FADH₂ produces 1.5 ATP. Therefore, the ATP yield from oxidizing one acetyl-CoA is
10 ATP. (Note: The previous calculation estimated 12 ATP).
Malate-Aspartate shuttle.
The reversible conversion of malate to oxaloacetate (OAA) can be used to shuttle molecules from the cytosol into the mitochondria, a
process known as the malate shuttle. To understand the malate shuttle, two key points must be considered. First, malate can cross the
mitochondrial membrane, while NADH and OAA cannot. As a result, this shuttle is used to transport electrons from NADH (which is
generated in the cytoplasm), into the mitochondria to enter the electron transport chain (ETC). Second, It also facilitates the transport of
OAA, synthesized in the mitochondria, into the cytoplasm for gluconeogenesis.
NADH, which is synthesized in the cytoplasm, cannot directly enter the
mitochondria to participate in the ETC for ATP synthesis. To transport electrons from
NADH into the mitochondria, cells use the malate shuttle. In the first step, OAA in
the cytoplasm is reduced to malate, a reaction that uses NADH and generates NAD+
in the process (NADH donates electrons to malate). Malate can then cross the
mitochondrial membrane through specific transporters and enter the mitochondria,
bringing the electrons inside. Once inside, malate is oxidized back to OAA, a
reaction that uses NAD+ (malate donates electrons to NAD+ to generate NADH,
which can enter the ETC). OAA in the mitochondria can also be converted into
aspartate, which can be transported back to the cytoplasm, where it is converted
back into OAA, thus regenerating OAA in the cytoplasm.
OAA synthesized in the mitochondria cannot directly enter the cytoplasm to
participate in gluconeogenesis. First, OAA must be converted into malate, which can
then leave the mitochondria through specific transporters. Once in the cytosol,
malate is converted back into OAA, which can then participate in gluconeogenesis.
Fumarase deficiency
Fumarase deficiency is a rare genetic disorder caused by mutations in the FUM1 gene, which encodes the enzyme fumarase. This enzyme
is crucial for the TCA cycle, catalyzing the reversible hydration of fumarate to malate. This condition disrupts the TCA cycle, leading to an
accumulation of fumarate, which impairs cellular energy production and can cause toxicity, particularly affecting the nervous system.
When fumarase is deficient, TCA cycle is disrupted, and fumarate accumulates in
the cells. This accumulation leads to several metabolic imbalances, including
impaired ATP production, as the TCA cycle cannot efficiently generate the highenergy molecules NADH, FADH₂, and GTP, which are essential for ATP synthesis
through the electron transport chain (ETC).
The buildup of fumarate also causes oxidative stress, which damages cellular
structures such as proteins, lipids, and DNA. Moreover, fumarate can interfere
with cellular signaling pathways, particularly in the regulation of histone
demethylases and the hypoxia-inducible factor (HIF) pathway, leading to
Fumarase
abnormal gene expression and further disruption of normal cellular functions.
The most significant impact of fumarase deficiency occurs in the nervous system,
particularly the brain. Neurons, which require high amounts of ATP for normal
function, are severely affected due to the energy shortage and the toxic effects of
fumarate accumulation. This results in neurodegeneration, developmental delay,
intellectual disabilities, seizures, and hypotonia (low muscle tone). The
accumulation of toxic metabolites leads to brain cell death and impaired neural
development, which is the hallmark of the disease. Other energy-demanding
tissues, such as muscles, are also affected, leading to muscle weakness and
movement disorders. Overall, fumarase deficiency leads to severe neurological
and metabolic consequences, with the brain being the most impacted organ.