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Lecture

Biochemistry

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Department
Biochemistry
Course
BCHM 2020
Professor
Mark Bayfield
Semester
Fall

Description
Section 3: Metabolism Metabolism: Synthesis and degradation of biopolymers  Anabolism – burns ATP; builds complex + + -overall reduction leads to “oxidation cofactors” …NAD NADP FAD -needs energy imput -make many diff. proteins from amino acids (divergence pathway)  Catabolism – gives off ATP; breaks down to simple compounds -oxidized until can no longer be oxidized - leads to formation of “reduced cofactors” … NADH NADPH FADH 2 -releases energy for production of ATP -many sugars can be broken down through same pathway (divergence pathway) -energy can be taken in form of ; fats, proteins, carbohydrates *(photosynthesis in plants) -3 stages: Glycolysis, Oxidative Metabolism, Carbohydrate Anabolism Chemical Reactions of Metabolism 1. Oxidation Reduction Reactions - most reduced carbon CH 4 - least reduced carbon CO 2 - energy comes from oxidation of high energy e- into less and less reduced forms - dehydrogenases  responsible for redox reactions *** - compound w. Hydrogen is reducing agent  allows compound B to gain e-‘s by being the donor - compound receiving Hydrogen is oxidizing agent  allows compound A to give away e-‘s by being accepto+ o major acceptor  NAD FAD (during oxid.) o major donor  NADH FADH (during2red.)  NAD – nicotinamide adenine dinucleotide FAD – flavin adenine dinucleotide 2. Group Transfer Reactions Phosphoryl Group o when transferred molecule w. phosphoryl group now has stored energy Acyl Group o from carboxylic to –SH group of CoA o creates thioester bond (high energy) o Acetyl group is most important carboxylic derivative … can be attached to CoA  acetyl-CoA **very reactive - all rxn’s occur to minimize ∆G o ∆G = ∆H-T∆S < 0 o spontaneous ∆G<0 non-spontaneous ∆G>0 (rxn. doesn’t happen) o Rxn. Reversible @equilib ∆G=0 o ∆G ∆ in free energy under standard conditions o entropy (S) increases w. volume o S & ∆g directly proportional; ∆G depends on concentration ° o ∆G = -RTInK (stneq Conditions) o ∆G >0 endergonic (requires Energy) o ∆G <0 exergonic (gives off energy) - * coversion of ATP to ADP + P … iives off a lot of energy (-30) Summary of Metabolism of Glucose o glucose metabolism into pyruvate o make glucose from pyruvate  Gluconeogenesis Lecture 10: Part I Glycolysis Steps 1-5: Energy Investment Step 2: Glucose to Glucose-6- Phosphate - phosphorylation … consume 1 ATP * - Hexokinase Step 2: Glucose-6-Phosphtae to Fructose-6-Phosphate -aldose to ketose (isomerization) -Glucose -6-Phosphate Isomerase ** In both steps Glucose and Glucose-6-Phosphate are in higher abundance than their products, b/c products are being constantly used allows rxn. to continue to shift to the right (trying to reach equilib. Step 3: Fructose-6-Phosphate to Fructose 1,6 –bisphosphate - second consumption of ATP * - phosphofructokinase [PFK] - phosphorylation at C 1 & 6 - very exergonic  irreversible in vivo o therefore primary regulation site of carbon flow in glycolysis o PFK allosteric enzyme … activity depends on availability of ATP & levels of other intermediates Step 4: Breakdown of Fructose1,6-bisphosphate into dihydroxyacetone phosphate (DHAP) and Glyceraldehyde-3-phosphate (GAP) - cleavage into 2 triose phosphates - highly endergonic … b/c of cell conditions rxn. Can proceed (∆G=0 & high [ ]) - Aldolase Step 5: Conversion of DHAP into GAP - triose phosphate isomerase - GAP is being consumed therefore rxn proceeds to right even tho it is endergonic - Rxn proceeds w. enediol intermediate * so far NET loss of 2 ATP; Gain 2 GAP ; 2 ADP … the following steps are x2 because we now have 2 molecules * Steps 6-10: Energy Generation Phase Step 6: GAP to 1,3 bisphosphoglycerate - Oxidation and Phosphorylation - GLyceraldehyde-3-phosphate dehydrogenase - Generates high energy compound - *req. coenzyme NAD to accept electrons … produces NADH (x2) * this step will indirectly make ATP * Step 7: 1,3 bisphosphate to 3-phosphoglycerate & ATP - directly make 1 ATP * (x2) - Phosphoglycerate Kinase - Substrate level phosphorylation Step 8: Phosphoglycerate to 2-phosphoglycerate - Moving phosphate from carbon 3 to carbon 2 - Phosphoglycerate mutase - Converting compound w. low phosphate transfer potential to high o Contains phosphorylated His residue rxn catalyzed through bis- phosphate itermediate o Rapid conversion of 2-phosphoglycerate moves rxn to right 9slightly endergonic) o ** Mg required Step 9: 2-Phosphoglycerate to Phosphoenolpyruvate (PEP) - dehydration rxn. - Enolase - Mg 2+ required * Step 10: Phosphoenolpyruvate & ADP to Pyruvate & ATP - second substrate level phosphorylation - transfer of posphoryl group to ADP - Pyruvate Kinase - Mg 2+ and K required ** BALANCE SHEET: gained 2 ATP & 2 NADH Aerobic (with O a2d Anaerobic (fermentation) Reduction Pyruvate (Anaerobic) - reduced by 2 NADH’s into lactate OR - 2 pyruvate  2 acetaldehyde + 2 CO 2 - reduced by 2NADH into ethanol -Glucose is very energetically favourable (spont. Even under standard conditions) 3 Major Steps: - rxn catalyzed by : (1)Hexokinase (2) phosphofructokinase [PFK] (3) pyruvate kinase Gluconeogenesis - occurs in liver in animals - many reactions are the reverse - irreversivle rxn’s must be bypassed ByPass #1: Pyruvate or Lactate - pyruvate into mitochondria - converted into oxaloacetate * spend ATP * - oxaloacetate converted to malate (b/c cant leave mito.) - malate eneters cytoplasm turned back into oxaloacetate o NET: have moved NADH from Mitochondria to cytoplasm - oxaloacetate converted back to PEP by carboxylkinase PEPCK & GTP … starting from lactate - get NADH from converting lactate back to pyruvate ( in cyto.) - make PEP from oxaloacetate directly in mitochondria ByPass #2 & #3 : - exergonic - req. hydrolysis of phosphoryl groups - #2 F 1,6 BisP + H 2  F6P + P i - #3 G6P  Glucose P + HIO 2 Regulation of Glucose Metabolism - High ATP; don’t need energy  favour glucogenesis - High AMP; need energy  favour Glycolysis Phosphorylation (controlled by glucagon & cAMP)  turns ON FBPase turns OFF PFK (PFK is inhibited by ATP binding) High Glucagon and cAMP (low glucose)  High Phosphorylation High Insulin (high glucose) Low Phosphorylyation Phosphorylated PFK-2 FBPase  low F2,6BP Dephosphorylated  High F 2,6 BP * F 2,6 BP activates PFK * Lecture 10: Part II Citric Acid Cycle - Pyruvate required further reduction to extract remaining energy - Oxygen final e- acceptor Substrates: Pyruvate, Oxygen, NAD, FAD, ADP Products: CO r2duced NADH, FADH , ATP 2 - Aerobic Metabolism  occurs in mitochondria (matrix / inner mitochondrial membrane) o Occurs through substrate channeling when enzymes are in close proximity allowing an efficient “chain like process to occur. Step 1: - pyruvate across inner mito. membrane by pyruvate translocase Step 2: - occurs in Pyruvate dehydrogenase comples - oxidation of pyruvate to Acetyl-CoA - get a molecule of CO 2 - thioester bond to CoA (accepts acetyl group) + - NAD  NADH (accepts e-‘s) Pyruvate Dehydrogenase Cycle Step 1: - pyruvate decarboxylated (by E1) … req. vitB1 & TPP - hydroxyethyl bound to TPP Step2: - hydroxylethyl oxidized into acetyl group by reducing disulphide bond of E2 - transfer acetyl group to E2 - *new thioester bond to the lipoamide Step 3: - Acetyl-CoA is formed - CoA acts as carrier for acetyl group Step 4: - FAD attactches to E3 & reduced to FADH 2 - FADH r2duces NAD to NADH to regenerate FAD (cycle) NET SUM: Pyruvate + CoA-SH + NAD  Acetyl-CoA + CO + NADH + H + 2 When reduced… - NAD  picks up 2 e- & 1 H + - FAD  picks up 2e- & 2 H + Citric Acid Cycle Step 1: Acetyl group joined to oxaloacetate - make citrate - citrate synthase - regenerates a CoA Step 2: Citrate Isomerized to Isocitrate - OH group moved to make 3° alcohol - Intermediate cis- aconitate - Done by aconitase - Easier to now break C-H bond vs. C-C bond in oxidation Step 3: Oxidation of Isocitrate to α-ketogluterate - done by isocitrate dehydrogenase - loss of CO 2 - reduction of NAD to NADH Step 4: Oxidation of α-ketogluterate to Succinyl-CoA - by α-ketogluterate dehydrogenase complex **similar to pyruvate dehydrogenase complex Result loss of CO , 2ed. Of NAD to NADH Step 5: Succinyl-CoA to Succinate - by succinyl-CoA synthase - regenerate CoA - forming ATP/GTP (substrate level phosphorylation)* Step 6: Oxidation Succinate to Fumarate - succinate dehydrogenase -
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