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The Krebs Cycle

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Question	Answer
Key points	Also known as citric acid or TCA cycle Final pathway of oxidative metabolism Produces most ATP Occurs inside mitochondria Produces reduced cofactors Several synthetic reactions Not a closed circle
Where does this fit in	In the course of substrate oxidation, pathways from all substrates converge on a small pool of common molecules Acetyl CoA or one of the krebs cycle intermediates
What does the krebs cycle do	Common intermediates can be completely oxidised to CO2 and H2O or used as starting materials for biosynthetic pathways C13 labelling used to trace carbons through the cycle NADH and FADH2 for oxidation and energy yield Produces energy in form of GTP
What are NADH and FADH2	Electron acceptors - become reduced Used in lots of metabolism NADH - pyridine dehydrogenases - more energy stored FADH2 - flavin dehydrogenases - less energy stored
Use of NADH	A substrate/product of reaction not a cofactor Diffuses away from the enzyme to complex 1
Use of FADH2	Covalently bound to enzyme as cofactor - cant diffuse to inner membrane - enzymes must be physically associated with membrane Lower reducing potential - cant reduce NAD so feeds electrons into ETC at ubiquinone at Complex 2
Brief overview	Acetyl CoA combines with oxaloacetate to form citrate Citrate forms isocitrate Decarboxylated to from alpha ketoglutarate then succinyl-CoA releasing Co2 and NADH SLP into succinate releasing GTP Converted to fumarate, malate and back to oxaloacetate
Enzymes involved from Oxaloacetate	Citrate synthase Aconitase Isocitrate dehydrogenase Alpha ketoglutarate dehydrogenase Succinyl CoA synthase Succinate dehydrogenase Fumarase Malate dehydrogenase
Key reactions	2 carbons enter cycle 2 molecules of CO2 released Substrate level phosphorylation 4 reduced cofactor molecules released
What energy does this produce	3 HADH - 7.5 FADH2 - 1.5 GTP - 1 so 10 ATP
Where does Acetyl CoA come from	Fatty acids - beta oxidation Ketone bodies - ketone body oxidation Amino Acids - amino acid degradation Sugars - glycolysis and PDH
Pyruvate dehydrogenase	Pyruvate converted to acetyl coA Released NADH and CO2
Pyruvate transport into mitochondria	Via specific pyruvate H symport
Oxidative decarboxylation of pyruvate	Enzymes - pyruvate decarboxylase, dihydrolipoyl transferase and dihyrdolipoyl dehydrogenase Cofactors - Thiamine pyrophosphate and lipoic acid Releases NADH and CO2
Pyruvate dehydrogenase complex	One enzyme complex contains all enzymes required for PDH A lipoamide arm bound to E2 guides the substrate from one subunit to the next
Why control PDH	Irreversible Costs energy Committed steps - point of no return Energy sensing Cannot resynthesis glucose past this point Inhibited by ATP and stimulated by ADP
Control of PDH	Inhibited directly by NADH and acetyl CoA Inactivated by PDH kinase (activated by ATP acetyl CoA and NADH inactivated by ADP pyruvate acetyl CoA and NAD) Activated by PHD phosphatase (activated by Ca, Mg and insulin)
Arsenic poisoning	Inhibits enzymes that use lipoic acid as cofactors pyruvate dehydrogenase, (branched chain) alpha ketoglutarate dehydrogenase Arsenic forms stable complex with thiol group of lipoic acid Inhibiting PDH increases pyruvate and lactate
Acetyl CoA + oxaloacetate	Combined by citrate synthase to form citrate Condensation reaction Inhibited by ATP, Citrate, NADH, succinyl CoA FA CoA Activated by ADP,
Citrate - formed isocitrate	Converted to alpha ketoglutarate by isocitrate dehydrogenase Oxidative decarboxylation Released NADH and CO2 Activated by ADP and calcium Inactivated by ATP and ANDH
Mutations in IDH	Mutations in IDH1/2 are found in 60-90% of secondary gliomas and 12-18% of leukaemia Originally thought to be blockage of TCA cycle leading to Warburg effect Shown that mutations lead to production of 2-HG - an oncometabolite
Alpha ketoglutarate	Converted to succinyl CoA by alpha ketoglutarate dehydrogenase Oxidative carboxylation Uses lipoic acid and thiamine pyrophosphatase as coenzymes Releases CO2 and NADH Activated by Ca Inactivated by ATP, GTP, succinyl CoA and NADH
BeriBeri	Thiamine deficiency Neurological and cardiac symptoms e.g. sheep like gait TPP is a prosthetic group of pyruvate dehydrogenase, alpha ketoglutarate dehydrogenase and transketolase Increase plasma pyruvate
Succinyl CoA	Converted to succinate by succinyl CoA synthase Thioesterase reaction Substrate level phosphorylation to release GTP
GTP	Phosphoryl donor in protein synthesis, gluconeogenesis Signal transduction Translocation of proteins into mitochondrial matrix Conversion to ATP via nucleoside diphosphokinase
Succinate	Converted to fumarate by succinate dehydrogenase Oxidation Releases FADH2
Succinate dehydrogenase	Embedded in inner mitochondrial membrane Directly linked to the electron transport chain Only enzyme common to both TCA cycle and ETC FAD is hydrogen acceptor as free energy not enough to reduce NAD 2 electrons from FADH2 transferred directly to QH2
Accumulation of succinate in ischaemia	Severe damage caused to ischaemic tissue on reperfusion Lack of O2 in ischaemia blocks SDH and leads to build up of succinate During reperfusion ETC overwhelmed by succinate leading to reverse electron transport causing production of ROSs
Malate	Converted to oxaloacetate by malate dehydrogenase Oxidation Releases NADH
Evidence - Szent Gyorgyi	Studied process of respiration on breast muscle of pigeons Minced the tissue and showed it took up oxygen rapidly Oxygen uptake was rapidly increased when carbohydrates of their C3 products were added Also true for C4 salts
Evidence - Krebs and Johnson	Animal tissue can make succinate if given pyruvate Succinate came from oxidation of citrate via a series of reactions shown in the liver Citrate did not disappear during this so must be reformed Via reformation from oxaloacetate
Why a cycle	Small amounts of cycle intermediates required to oxidise large amounts of acetyl CoA Only small amount of oxaloacetate needed as constantly regenerated If enzymes blocked becomes an open pathway - need a source of intermediates
Control via calcium	Activation of receptor leads to calcium release from ER stored Calcium in matrix activates pyruvate dehydrogenase, isocitrate dehydrogenase, alpha ketoglutarate dehydrogenase Specific transport alters mitochondrial calcium to refelect cytoplasmic change
Other roles of the TCA cycle	Route of disposal for amino acids and odd chain fatty acids e.g. his, pro, gln, arg feed into alpha ketoglutarate Intermediates are starting points for biosynthesis e.g. citrate for fatty acids and oxaloacetate for glucose Linked to lots of reactions
Disadvantages of the cycle	Removal of intermediates can deplete levels e.g. for biosynthesis Need anaplerotic reactions to maintain conditions AAs form alpha ketoglutarate, fumarate and oxaloacetate Valine, isoleucine and odd chain FAs form succinyl CoA Pyruvate - oxaloacetate