TBL10 Flashcards
TCA Cycle and Ox. Phos
pyruvate dehydrogenase complex
thiamin (Vitamin B1)-dependent, essential for glucose oxidation in the brain. Deficiency leads to accumulation of lactate=> lactatic acidosis
pyruvate oxidation
Gluconeogenic amino acids
from protein metabolism
Alanine, cysteine, glutamic acid, glycine, serine, threonine, tryptophan
pyruvate oxidation
How to make pyruvate
Glucogenic amino acids (protein metabolism) and glycerol (from fat metabolism) –> Pyruvate
Anaerobic glycolysis
state
during cellular hypoxia or when energy demand is rapidly increased to exceed rate at which ox phos can provide sufficient ATP
short intense exercise (10 sec-2min)
Lactate dehydrogenase
Anaerobic glycolysis
pyruvate+ NADH–> lactate +NAD+ +2ATP
Gluconeogenesis pathway
glucose is formed from non-hexose precursors such as glycerol, lactate, pyruvate, and glucogenic amino acids
precursors
Gluconeogenesis
glycerol, lactate, pyruvate, and glucogenic amnio acids n
Ketogenic Amino Acids
Relationship of Acetyl CoA with TCA Cycle
Phe, Leu, Isn, Lys,Thr, Trp, Tyr
How to form Acetyl CoA
Relationship of Acetyl CoA with TCA Cycle
Ketogenic Amino Acids + FAs
Acetyl CoA can:
Relationship of Acetyl CoA with TCA Cycle
- relate carbohydrate, protein, and lipid metabolism to each other
- enter TCA cycle
- be involved in synthesis of Acetylcholine, cholesterol, FAs, and ketone bodies
Where does Krebs Cycle take place?
mitochondrial matrix
metabolic pathway of TCA Cycle
consumes acetate as Acetyl CoA and 2H2O
generates: 3NADH, 1FADH2, 1GTP, net yield 12 ATP, oxaloacetate
NADH
fed into Ox. phos. during ETC
NADH and FADH2 are essential for ox. phos.
FADH2
transferred from ETC
covalently attached to succinate dehydrogenase
facilitates transfer of e- to Co-Q/ubiquinone
TCA Cycle Intermediates
Acetyl-CoA
- can be converted to: AAs, FAs, cholesterol, ketone bodies, acetoacetate,3-beta-hydroxybutyrate, and acetone
- synthesizes: Acetylcholine, cholesterol, FAs, ketone bodies
TCA cycle intermediates
Ketone Bodies
- produced from FAs by liver
- converted to Acetyl-CoA, enters citric acid cycle
- source of energy in prolonged fasting
TCA cycle intermediates
alpha-ketoglutarate
directly used to form AAs (glutamate to GABA, Gln, Pro, Arg)
TCA cycle intermediates
Succinyl CoA+Glycine
form poryphyrin/heme part of Hgb
TCA cycle intermediates
Succinyl CoA
- converts into succinate, lead to increased formation of GTP
- Succinyl CoA+Glycine–> used in poryphyrin/Heme part of Hgb
TCA cycle intermediates
OXALOACETATE
Phosphoenolpyruvate
TCA cycle intermediates
Protons-How generated?
NADH later use in ox.phos
Krebs cycle activators
Glutamine, Glutathione, Fe, NADH, Carnosine, exercise
Krebs cycle inhibitors
Aconitase inhibition:Zn excess and other inhibitors
Metals: Pb, Cd, Cr, Mn, Al, Fe excess
Metformin
Vitamin B12 Deficiency
Terminal electron acceptor of ETC
Aerobic conditions
O2
electron acceptor of ETC (anaerobic conditions)
sulphate
ETC Complex I
NADH Dehydrogenase
- accepts electrons from TCA cycle’s electron carrier NADH
- NADH reduces FMN to FMNH2, then oxidized to Ubiquinone Coenzyme Q
- Reduced product: Ubiquinol QH2
Complex I pathology
Rotenone
Pesticide, fish poison
inhibits NADH-Ubiquione Oxidoreductase
Symptoms: vomiting, incoordination, convulsions, CNS depression and respiratory distress, bradycardia, arrythmia
ETC Complex II
Succinate Dehydrogenase
ETC Complex III
Complex III Inhibitors: Dimercaprol
chelating agent used to treat acute poisioning by lead, mercury, arsenic, or gold
ETC Complex III
Complex III Inhibitors: Naphthoquinone
- analog of coenzyme Q,
- competitive inhibition of active site of ubiquinone
- treats pneumocystis pneumonia and malaria
ETC Complex 3
Antimycin A
- binds Q site of cytochrome c reductase
- inhibits oxidation of ubiquinol to ubiquinone
- no production of ATP, disrupts formation of proton gradient
- may prematurely leak electrons to O2 resulting in formation of free radicals
Complex IV
Cytochrome C Oxidase
- contain Cu ions and heme groups
- 4 e- removed from Cytochrome C and transferred to O2 and protons producing 2 H2O
- 8H+ removed (4 translocated across membrane) to electrochemical gradient
Complex iV
Cytochrome C Inhibitors
- CO, HS, Azide, Cyanide
Complex IV
Cytochrome C Inhibitors: Cyanide
- attaches to iron, disrupts ETC
Cyanide Poisoning
hypoxia leads to neurologic/CV compromise: headache, vertigo, confusion, pallpitations, shortness of breath, vomiting, seizures, low BP, cardiac arrest, lactic acidosis
Chemiosmosis
Chemiosmotic coupling hypothesis
ETC and OxPhos are coupled by electrochemical proton gradient through ATP Synthase
1. a membrane impermeable to protons
2. electron treansport by cellular respiratory chain pumps protons out of mitochondria
3. proton flow into the mitochondria depends on presence of ADP and Pi inside mitochondria
4. reversible ATPase activity
chemiosmosis
transport of e-
NADH+2H+ + 1/2O2–> H2O+ NAD
I Glucose produces
- 38 ATP: 2 from glycolysis, 2 from TCA, 34 from ETC
Uncoupling of ETC and OxPhos
- thermogenin
- will result in increased ADP and Pi in mitochondria
- OxPhos produces ROS
Drugs that inhibit Ox Phos
Oligomycin A (antibiotic)
- selectively inhibits ATP synthase by blocking its proton pump
- induces apoptosis
Drugs that inhibit Ox Phos
2,4-Dinitrophenol
- antiseptic, non-selective bioaccumulating pesticide
- inhibits ox phos
- disrupts proton gradient, causes uncoupling
PDHC Deficiency
- X-linked, neurodegenerative
- Leigh Syndrome
- Fumarase Deficiency
- mutations of IDH
Leigh Syndrome
Fumarase Deficiency
