TCA Cycle Flashcards by Lily Nunvar

The TCA cycle _____ two carbons of acetate from acetyl CoA and generates NADH and FAD2H. In anabolism, it generates key intermediates for _____, _____, and _____

Oxidizes
Gluconeogenesis
Fatty acid synthesis
Amino acid synthesis

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The TCA cycle occurs in the ___ of the mitochondria. The outer membrane is permeable to most molecules. The inner membrane is very ____. This allows a proton concentration gradient to be established across the ____ ___ of the mitochondria

Matrix
Impermeable
Inner membrane

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The matrix naturally has ___ proton concentration. The inter-membrane space has naturally ____ proton concentration

Low
High

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The electron transport chain requires genes and proteins from both ____ and ____ DNA

Nucleus
Mitochondrial

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Mitochondrial DNA is more similar to _____ DNA then nucleus DNA

Prokaryotic

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Mitochondrial DNA is _____ because it is naked, and not bound to histones in a chromatin structure. It is exposed to hire concentrations of ____ ____ ____. The mitochondrial DNA polymerase has limited ability to repair DNA damage.

Hypermutatable

Reactive oxygen species

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Mitochondrial DNA is dynamic. There are multiple ____ of the mitochondrial DNA to help push back from the hypermutability, especially in energetics cells like ___ cells

Copies
Muscle

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Many symptoms of mitochondrial disease are ____ due to energy starvation during fetal development

Neurological

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Glycolysis occurs in the ____. Pyruvate, dehydrogenase, and the TCA cycle occur in the _____.

Cytosol
Mitochondria

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Pyruvate is transported to the mitochondria via the _____ ____ ____ which acts as a heterodimer of two subunits: ____ and ____
MPC is located on the ____ ____ of the mitochondria.

Mitochondrial pyruvate carrier (MPC)
MPC1 and MPC2
Inner membrane

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Inherited mutations in the mitochondrial pyruvate carrier causes ____ _____

Lactic acidosis

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____ ____ is the link between glycolysis and the TCA cycle. It has four subunits. E1 subunit is ____ ____, with a thiamine pyrophosphate. E2 is a _____ with Lipoate and CoA. E3 is a ____ with FAD and NAD+. Keto acid dehydrogenase and branch chain ketoacid dehydrogenase share a similar organization.

Pyruvate dehydrogenase
Pyruvate decarboxylase
Transacetylase
Dihydrolipoyl dehydrogenase

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Pyruvate dehydrogenase is regulated by reversible _____. When activated the ___ ___ will proceed. When inhibited, pyruvate will be converted into ____.

Phosphorylation
TCA cycle
Lactate

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Pyruvate dehydrogenase is regulated by phosphorylation and dephosphorylation of ____ residues in ____ alpha subunits

Serine
E1

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Pyruvate is converted into ____ by pyruvate dehydrogenase which then bonds to coenzyme A, forming ____

Acetate
Acetyl CoA

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All reactions of the TCA cycle take place in the ____ ____

Mitochondrial matrix

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Overview of TCA cycle:

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____ ____ is the key rate limiting enzyme in the TCA cycle

Isocitrate dehydrogenase

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The reaction from acetyl-CoA to citrate is energy yielding however, the following reaction is not energetically favorable. This allows for ____ to build up and be used as an intermediate for other biosynthetic reactions. This is like wise for ____.

Citrate
Malate

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First step:
The enzyme ____ ____ hydrolyzes, the Theoester bond of acetyl CoA to join acetate and oxaloacetate, forming ____. Citrate has three carboxylic acid groups, making it a tricarboxylic acid.

Citrate synthesis
Citrate

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Second step:
The enzyme ____ catalyzes a two step isomerization to convert citrate to _____, which is a tricarboxylic acid

Aconitase
Isocitrate

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Third step:
____ ____ catalyzes this oxidative decarboxylate, isocitrate is converted into ____. It uses NAD+ and creates____. IDH1 in the cytosol and IDH2 in the mitochondria catalyze the same reaction but use ____ instead

Isocitrate dehydrogenase (IDH3)
Alpha-ketoglutarate
NADH
NADP+

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Isocitrate dehydrogenase removes an ____ group from 6 carbon Isocitrate forming the 5 carbon alphaketoglutarate. _____ is a byproduct

Carboxyl
CO2

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Fourth step:
_______ _____ catalyzes the final oxidative decarboxylation, forming _______ from alpha ketoglutarate. ____ and ____ are byproducts

This product is then added to acetyl CoA similar to pyruvate dehydrogenase enzyme.

Alpha-ketoglutarate dehydrogenase
succinyl CoA
NADH
CO2

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Alpha ketoglutarate dehydrogenase removes a carboxyl group from the ____ carbon alpha-ketoglutarate forming the ___ carbon succinyl CoA. At this point ___ carbons have been released as carbon dioxide, but not the same carbons that entered as acetyl CoA

5 4 2

Review: Look at cofactors

Fifth step: _____ ____ cleaves the Theoester bond, linking succinate and CoA this is a strongly extra Gondek reaction and the enzyme uses the energy to catalyze substrate level phosphorylation of GDP to make GTP. The end product is ____.

Succinate thiokinase

Sixth step: ____ _____ oxidizes succinate to introduce a double carbon-carbon bond forming ____. FAD is reduced to ___. Succinate dehydrogenase is a component of the electron transport chain transferring electrons from FAD2H to _____.

Succinate dehydrogenase Fumarate FAD2H Coenzyme Q

Seventh step: _____ _____ it’s a proton and hydroxyl from water to fumarate double bond forming ____.

Fumarate hydratase Malate

Eighth step: ____ ____ oxidizes malate’s hydroxyl to a keto group forming _____ and reducing NAD+ to NADH in the process

Malate dehydrogenase Oxaloacetate

In the TCA cycle overall, 1 two carbon acetyl group and two waters become 2 carbon dioxides. The net production goes on to make ___ ____

10 ATP

In the liver, in the fasted and starved states, ____ is high because of fatty acid Beta-oxidation. This prevents acetyl CoA from oxidation in the ____ ___, and drives it towards ketone body synthesis

NADH TCA cycle

Isocitrate dehydrogenase is the rate limiting step of the TCA cycle, activity is regulated by the ratio of ____ to ____ in the mitochondria. ADP binding to one subunit changes the conformation of other subunits to alter their affinity for substrate.

ADP ATP

The presence of ADP results in more ___ ____ enzyme activity, up regulating the TCA cycle. ADP is an _____ ____

Isocitrate dehydrogenase Allosteric activator

_____ acts as an Allosteric activator of NAD+ dependent Isocitrate dehydrogenase (IDH3). This is a ____ ____ regulation

Citrate Feedforward activation

Which amino acids can be generated from the TCA cycle intermediates through transamination reactions?

Aspartate and glutamate, their side chains can be transaminated, transaminases use vitamin 6 as a cofactor

____ reactions increase the capacity of the TCA cycle. Every time an intermediate leaves the cycle, the capacity decreases. ____ reactions help replenish the TCA cycle

Anaplerotic Anaplerotic

_____ participates in fatty acid synthesis when it leaves the TCA cycle _____ participates in amino acid synthesis and is a Neuro transmitter ____ participate in heme synthesis _____ participates in gluconeogenesis _____ participates in amino acids synthesis

Citrate Alpha-ketoglutarate Succinyl-CoA Malate Oxaloacetate

____ ____ is a Anaplerotic reaction that converts pyruvate to oxaloacetate which can then join acetyl CoA to form citrate

Pyruvate carboxylase

______ ____ pathway in muscles is a type of Anaplerotic reaction. When muscle cells are working, they require a lot of ATP. ____ ____ converts a AMP to inosine monophosphate (IMP). This results in an increase in blood _____. ____ _____ takes a carbon from Aspartate to form fumarate, regenerating ____.

Myoadenylate deaminase Myoadenylate deaminase Ammonium Adenylsuccinate AMP

______ ____ _____ is from inherited mutations in the gene coding the muscle specific AMPD1 isoform of AMP deaminase results in an inactive enzymes. This makes individuals ___ intolerant because the TCA Cycle can’t be replenished in response to work

Myoadenylate deaminase deficiency Exercise

TCA cycle intermedius influence _____ Gene expression through epigenetic regulation. _____ is the substrate for histone acetyl transferences. ____ and ____ block histone and cytosine demethylases

Nuclear Acetyl CoA Succinate fumarate

If there is a mutation in succinate dehydrogenase, there is a buildup of ____ which promotes the methylation of nuclear DNA leading to changes in transcriptional patterns, which can ultimately lead to ____

Succinate Cancer

____ ____ is a tumor suppressor.

Succinate dehydrogenase

____ _____ _____ uses molecular oxygen to hydroxylate the methyl carbon from lysine. During this reaction, alpha-ketoglutarate is decarboxylated to ____. Therefore, An increase in succinate promotes the methylation of lysine rather than the demethylation

Jumanji domain demethylases (JHDM) Succinate

2-hydroxyglutarate is an ______, meaning it interferes with the function of alpha-ketoglutarate utilizing dioxygenase enzymes, sometimes leading to cancer

Oncometabolite

Gain of function mutations in the ____ ____ causes the enzyme to run in reverse reducing alpha-ketoglutarate to 2-hydroxyglutarate

Isocitrate dehydrogenase

2-hydroxyglutarate acts as a ____ ____ for me deoxygenated, as such as the Jumanji domain lysine demethylases, causing _____ within the cell

Competitive inhibitor Hypermethylation

Inhibition of ____ _____ and ____ ___ causes hypermethylation and changes the transcriptional program of the cell at specific genes that promote proliferation and inhibit differentiation and apoptosis. Leading to uncontrolled cell division and cancer

Lysine demethylases (KDMs) Cytosine demethylases (TET2)

______ of proline and lysine residues in _____ is also dependent on alpha-ketoglutarate dependent dioxygenases.

Hydroxylation Collagen

Alpha-ketoglutarate dependent dioxygenases regulate diverse processes with the cell. When mutations in ____ _____ occur, 2-hydroxylglutarate accumulates causing changes in gene expression and oxygen sensor which can contribute to cancer. Increased ____ inhibits all of these reactions because it is the product of Isocitrate dehydrogenase

Isocitrate dehydrogenase Succinate

Succinate dehydrogenase acts as a tumor suppressor, it’s substrate, succinate, builds up and inhibits ______ ____ ____ such as HIF prolyl hydroxylase. This stabilizes HIF and promotes a pro survival metabolism

Alpha-ketoglutarate dependent dioxygenases

____ ____ are also alpha-ketoglutarate dependent dioxygenases. In oxygen sensing, _____ is a substrate for prolyl hydroxylation, which signals its destruction in the presence of oxygen

Prolyl hydroxylases (PHDs) Hypoxia inducible factor HIF

Many ____ ____ inhibit alpha-ketoglutarate dependent dioxygenases. Mutations in the ___ ____ enzymes cause a build up of these oncometabolites and contribute to cancer

Tricarboxylic acids TCA cycle

Model of pyruvate dehydrogenase cofactors: