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The Citric Acid/Krebs Cycle

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on 27 November 2013

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Transcript of The Citric Acid/Krebs Cycle

Limited research
Severity of the disease
An inability to complete the citric acid cycle causes ATP deficiency and inability for cells to complete vital cellular functions
Image by Tom Mooring
Chemical Reactions
The Citric Acid/Krebs Cycle
This 4C molecule combines with Acetyl-COa (2C) to make Citrate
6C molecule
Extreme Muscle Fatigue
buildup of lactic acid resulting in acidosis
acid in body fluids & increased Ca2+ and K+
depressed nervous system & muscle fatigue
muscle protein loss if prolonged
chronic lung disease
respiration O2 (not CO2) driven
CITRATE
What Are The Chemical Reactions?
by
David Hyatt
Amanda Little
Timothy Wang
Geoff Ibe
Diseases & Disorders
Citric acid cycle diseases are not well understood
Prolonged exercise or physical stress
Diagnosis
arterial blood gas analysis
basic metabolic panel

Possibly due to:
Citric Acid Cycle Intermediates
Malic Acid
Fumaric Acid
Both thought to be linked to psoriasis
Immune related disease affecting the skin, causing an overproduction of skin cells, including red, dry and itchy patches accumulated on the body
Genetic Disorders & Enzymes
Pyruvate dehydrogenase complex disorder
(PDHA)
One of the more common genetic disorders
Series of 3 enzymes that transfer pyruvate into acetyl-CoA
pyruvate dehydrogenase, dihydrolipoyl transacetylase, dihydrolipoyl dehydrogenase
Insufficient enzymes results in inadequate energy to the cells
Long term, degeneration and underdevelopment of tissues, with most profound effects seen in the brain and CNS including:
underdevelopment between two hemispheres
lack of myelin surrounding neurons
dysmorphic facial features
Prognosis
varies depending on severity of the disorder
As individual grows, they may need increased PDHA and see increased effects later in life
Individual with no ability to synthesize will see progressed symptoms sooner
Genes involved in synthesis of fumarase & succinate dehydrogenase linked to leukodystrophy and Leigh Syndrome
Leukodystrophy - group of disorders involving the degeneration of white matter in the brain and degeneration of myelin sheath
degeneration & underdeveloped brain and CNS sys
affects movement, speech, hearing, ability to eat
Leigh Syndrome - affects the CNS
degeneration & underdeveloped brain
diarrhea, dysphagia (trouble swallowing), muscle debilitation
Impaired energy metabolism indicators of Alzheimer's disease
Treatments
due to rarity of many of the disease states involving the citric acid cycle, treatments are in their infancy
Most treatments are very specific, tailored to the specific symptoms exhibited
Some involve vitamin and amino acid therapy
Supplementing enzymes
Anti-fatigue buffers (ie. potassium and sodium phosphate)
Additional research is needed to better understand the disorders and disease states associated with the citric acid cycle
Starts with Aceytl-CoA + Oxalocetate to Citrate
Succinyl-CoA back to Oxaloacetate
Products from reactions
ISOCITRATE
6C
NAD+ -> NADH
1 CO2 is produced
Alpha-Ketoglutarate
now a 5C molecule
NAD+ -> NADH
1 CO2 produced
FUMARATE
4C
H20 added
Citrate Synthase
Oxaloacetate
Aconitase
Isocitrate Dehydrogenase
(IDH)
Alpha-Ketoglutarate Dehydrogenase
SUCCINYL-CoA
4C
Succinyl CoA Synthase
SUCCINATE
4C
1FAD+ -> FADH
GDP -> GTP is made (basically ATP)
Succinate Dehydrogenase
(Succinate DH)
Fumarase
Malate Dehydrogenase
ACETYL-CoA
What Are Implications/Consequences of CAC?

First, two carbons from Cirtrate are oxidized to CO2
MALATE
4C
NAD+ -> NADH
Second, Succinyl-CoA is converted back to Oxaloacetate to start cycle again
Only 1 ATP made, but creates (3) NADH and (1) FADH for ETC with (2) CO2
C.I.A. Sucks-CoA. Sucks. F.M.(oxy)L.
where does Citric Acid Cycle occur?
In the cytoplasm
for prokaryotes.
where does the Citric Acid Cycle Occur?
in the matrix of mitochondria
for eukaryotes.
Examples of Inhibitors
Examples of Activators
-NADH

-Citrate (also inhibits the
precursor to pyruvate)

-ATP

-succinyl-CoA
-Ca++ (activates pyruvate DH, citrate synthase, isocitate DH, alpha-ketoglutarate DH)

-ADP
Regulation of the TCA cycle
largely determined by product inhibition; and substrate availability like citrate, isocitrate, alpha-ketoglutarate, ADP, acetyl-CoA
there are 4 regulatory checkpoints in the cycle
Checkpoint 1
Checkpoint 2
Oxaloacetate + Acetyl CoA + H2O --> Citrate + CoA-SH (citrate synthase)
Checkpoint 3

Citrate --> cis-Aconitate + H2O (aconitase) + isocitrate
Checkpoint 4
Isocitrate + NAD+ Oxalosuccinate + NADH + H + (isocitrate dehydrogenase)
Oxalosuccinate alpha-Ketoglutarate + CO2 (isocitrate dehydrogenase)



generates NADH (equivalent of 2.5 ATP),



α-Ketoglutarate + NAD+ + CoA-SH --> Succinyl-CoA + NADH + H+ + CO2 (alpha-ketoglutarate dehydrogenase)


Irreversible synthesis of substrate acetyl-CoA from pyruvate


oxalosuccinate
Substrates
Products
acetyl CoA
citrate
isocitrate
oxalocitrate
citrate
isocitrate
alpha-oxalocitrate
succinyl-CoA
Introduction to the Citric Acid Cycle
Sources of Acetyl-CoA
Acetyl-CoA
Overview
Also known as the Krebs Cycle, or TCA (Tricarboxcylic Acid) Cycle
Ultimately identified in 1937 by Sir Hans Adolf Krebs
2 main purposes:
-increase the cell's ATP producing potential
-provide the cell with precursors that can be used depending on the needs of the cell
Amphibolic
Acetyl-Coenzyme A (Acetyl-CoA) initiates the Citric Acid Cycle
The overall reaction for the citric acid cycle per pyruvate is: Acetyl-CoA + 3 NAD+ + FAD + GDP + Pi + 2 H2O ---> CoA-SH + 3 NADH + 3 H+ + FADH2 + GTP + 2 CO2
Amphibolic Properties
Anabolic Aspects:
Citrate --> Lipids (Fatty acids and Cholesterol
Oxaloacetate --> Glucose
Oxaloacetate --> Amino Acids
Alpha-Ketoglutarate --> Amino Acids

Anapleurotic Reactions of Citric Acid Cycle
Anapleurotic reactions: Reactions that replenish CAC intermediates.

Ex.
Pyruvate --> Oxaloacetate (by Pyruvate Carboxylase)
Aspartate --> Oxaloacetate
Glutamate --> Alpha-Ketoglutarate
Catabolic Aspects: Involved in the series of reactions used generate energy through the oxidation of acetate derived from carbohydrates, fats and proteins.
Transamination:
Aconitase deficiency
mutation involving Fe-S cluster
involved in oxidation/reduction rxn
symptoms:
myopathy - muscle disease
exercise intolerance - unable to exercise to normal levels
severe post-exercise pain & fatigue
Linked to diabetes, but circumstances unknown
Citrate Synthase
no diseases effectively linked to citrate synthase, probably because organism will not produce enough energy to survive embryogenesis.
Isocitrate dehydrogenase
mutation at active site (Arg 132 & 140)
found in some Gliomas
tumor that begins in the brain or spinal cord
Unknown cause or association
treatments:
topical creams
phototherapy (UV light)
methotrexate, cylosporine (immunosuppresants) & retanoids (vit A)
vegetarian diets, fish oil
Acronym
Full transcript