TCA Cycle Flashcards
Hematopoietic stem cell transplantation has been successfully used in a small number of extremely compromised pediatric patients with
Pyruvate kinase deficiency
Shows the signs of muscle weakness, hyperuricemia, and hemolytic anemia
PFK-1 deficiency
Increased serum creatine from muscle breakdown is also a sign of
PFK-1 deficiency
Developmental delay in the newborn and microcephaly. Neurologically these infants will present with repeated seizures and may also exhibit muscle spasticity and hypotonia
GLUT 1 deficiency
How can we treat a GLUT-1 deficiency?
Ketogenic diet
An autosomal dominant mutation, which results in an increased blood glucose, needed to trigger insulin secretion
Glucokinase Deficiency
This condition of glucokinase deficiency is termed
Maturity Onset Diabetes of the Young (MODY)
Signs/Symptoms: Usually minimal. Heterozygotes typically exhibit increased blood glucose levels
MODY
MODY homozygotes can present with
Neonatal diabetes
Pyruvate and lactate are the formal end points for
Aerobic and anaerobic glycolysis respectively
In the liver, Pyruvate can be converted to one of which two things?
- ) Oxaloacetate (gluconeogenesis)
2. ) Acetyl CoA (TCA)
Aerobic glycolysis formally ends with the production of pyruvate. With the linker reaction converting pyruvate to
Acetyl CoA
Pyruvate is converted to Acetyl CoA by
Pyruvate Dehydrogenase
Under conditions of immediate need
for ATP, acetyl CoA is directed into the
TCA Cycle
Pyruvate in the cytoplasm is transported into the mitochondria and is converted to the two-carbon acetyl CoA by the pyruvate dehydrogenase complex. This is an
Irreversible reaction
The irreversible conversion of pyruvate to acetyl CoA produces
NADH and releases the first free CO2
The pyruvate dehydrogenase complex is made up of
3 enzymatic activities and 5 co-factors
What are the 3 enymatic activities of the pyruvate dehydrogenase complex?
- ) Pyruvate decarboxylase,
- ) Lipoamid reductase transacetylase
- ) Dihydrolipoyl dehydrogenase
What are the 5 cofactors of the pyruvate dehydrogenase complex?
Thyamine pyrophosphate, FAD, NAD, CoA, and lipoic acid
One of three regulatory steps in the TCA cycle, pyruvate dehydrogenase is a regulated enzyme, one of three that has a strong influence on flux through the
TCA cycle
While the pyruvate –> acetyl CoA step does not commit acetyl CoA to the TCA cycle, it does decide the fate of
Pyruvate
Pyruvate dehydrogenase is negatively regulated by
Acetyl CoA and high levels of NADH
ATP, Acetyl CoA and NADH collaborate on inhibition of
Pyruvate Dehydrogenase
Stimulation of a kinase, which phosphorylates the dehydrogenase by these small molecules, inhibits
Pyruvate dehydrogenase complex
This novel kinase is inhibited by high levels of
-allows a competing phosphatase to dephosphorylate and thus activate the pyruvate dehydrogenase complex
CoA, NAD+, or Pyruvate
This phosphatase is stimulated by
Calcium
The TCA cycle is best thought to begin with the conversion of acetyl CoA and oxaloacetate (another TCA intermediate) to
Citrate and free CoA
Therefore, the pyruvate dehydrogenase complex reactions are considered a link between glycolysis and the TCA cycle, and the next-in-line reaction, catalyzed by the enzyme
Citrate synthase
Citrate is then isomerized to isocitrate by the enzyme
-an irreversible reaction
Aconitase
This sets the stage for two successive
Oxidative decarboxylations
First, isocitrate dehydrogenase converts isocitrate to a-ketoglutarate with the production of
1 CO2 and the reduction of NAD to NADH
Alpha-ketoglutarate is then converted into
-catalyzed by a-ketoglutarate dehydrogenase complex
Succinyl CoA
his reaction releases the second
-also reduces one NAD to NADH
CO2
Both of these dehydrogenases are subject to regulation, and join with citrate synthase to be the major sites for regulation of flux through the
TCA Cycle
The conversion of succinyl CoA to succinate is the site for another substrate level phosphorylation, this time with the production of
GTP
This step in the TCA cycle is catalyzed by
-releases free CoA
Succinyl CoA Thiokinase
The GTP formed by the reaction catalyzed by succinyl CoA thiokinase can later be used to convert ADP to ATP via the enzyme
Nucleotide diphosphate kinase
Succinate is then converted to fumarate via
Succinate dehydrogenase
The conversion of succinate ot fumarate produces
FADH2
Adds a water molecule across the double bond of fumarate to produce L-malate
Fumarase
Finally, L-malate is oxidized to
-Produces NADH
Oxaloacetate
L-malate is converted to oxaloacetate by the enzyme
Malate dehydrogenase
We have thus replenished the oxaloacetate that was recruited, with acetyl CoA, at the beginning of our cycle, by
Citrate Synthase
When all is said and done, the TCA cycle produces
2 CO2, 3 NADH, 3 H+, FADH2, GTP, and CoA
In oxidative phosphorylation, how many ATP molecules are produced from the following?
- ) NADH
- ) FADH2
- ) 3 ATP per NADH
2. ) 2 ATP per FADH2
How many total ATP are produced as a result of the TCA cycle?
12
The three enzymes that regulate flux through the TCA cycle are?
Citrate synthase, isocitrate dehydrogenase, and a-ketoglutarate dehydrogenase
Both glycolysis and the TCA cycle will halt if we can not recycle?
NAD and FAD
The principal players of NAD and FAD recycling are O2, Pi and the ratio of ADP (and Pi) to ATP, in a process called
Respiratory Control
A TCA intermediate that functions as an allosteric regulator of glycolysis
Citrate
In an effort to conserve glucose for other tissues unable to metabolize fats such as the brain and red blood cells, high concentrations of citrate will shut down
Glycolysis
This doesn’t mean the cell is inert; it could still rapidly metabolize fatty acids via
B-oxidation and the TCA cycle
Is Citrate able to shut down glycolysis in the liver?
No
In the liver, the allosteric inhibition by citrate is trumped by the allosteric activation of
PFK-1
Insulin and glucagon play no direct regulatory roles in the steps of the
TCA cycle
In fact, neither glucagon nor insulin directly regulate any events in the
Mitochondria
There are several mechanisms for pyruvate dehydrogenase complex deficiency. One of them is X linked mutation of the E1 subunit of the
Pyruvate Dehydrogenase Complex (PDC)
Binds to E1 subunit of PDC, therefore in some cases, its affinity to the enzyme is reduced
Thiamin
Patients with this kind of mutation may benefit from high dose of
Thiamin supplementation
Lactic acidosis and neurological symptoms are signs of
PDC deficiency
The lactic acidosis in PDC deficiency is due to the shunting of
Pyruvate to lactate
Can increase activity of the remaining functional PDCs in patients with PDC deficiency and has been shown to improve patient symptoms
Thiamine supplementation
Disorders of the TCA cycle enzymes are
Rare
The various deficiencies in enzymes of the TCA cycle have been grouped as variants of
Leigh Disease
Patients typically begin showing symptoms shortly after birth with few surviving childhood
Leigh disease
LActic acidosis and neurological problems are frequently observed with
Leigh disease
Compared to inborn errors of the TCA cycle nutritional deficiencies or toxin exposure is a much more common presentation of
TCA cycle dysfunction
Interferes with the E2 subunit of dehydrogenase enzymes resulting in a clinical picture similar PDC deficiency with patients showing signs of lactic acidosis and neurological impairment
Arsenic Poisoning
The classic indication of arsenic poisoning is
-from oxidized arsenic
Garlic Breath
Essential for dehydrogenase enzymes e.g. PDC, alpha ketoglutarate dehydrogenase complex and branched-chain alpha keto acid dehydrogenase
Vitamin B1 (Thiamin)
Its deficiency leads to impaired carbohydrate, lipid and amino acid metabolism
Thiamin
Progressive heart failure resulting in edema, dyspnea, increased JVP and fatigue are signs of
Wet Beriberi
Constellation of neurological symptoms following peripheral nerve damage: Decreased Reflexes, paresthesia, loss of coordination, confusion etc are signs of?
Dry Beriberi
