1. PDH. The Chemistry

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1 A Respiration: xidative metabolism of all metabolic fuels (carbohyrates, fats) via etyl oa -- Mitochondrial reactions -- Require (or another e acceptor) -- We can metabolize carbohydrates anaerobically or aerobically -- We can only metabolize lipids aerobically tages: 1. PD: P. TA: 3. Electron transport and oxidative phosphorylation Think retrosynthetically oa + These went to Introducing: The Mitochondrion uter membrane ytoplasm very porous xidation of FAD and IM (inner membane space) e transport oa + ATP/GTP + + FAD. TA ycle - verview -- receives etyl oa from PD via PD A (4) oxaloacetate Glycolysis FA xidation (later) oa () TA (Krebs) ycle (8 teps) Note: The cycle is catalytic - carbons go in; carbons go out; the [intermediates] do not change - they are the "catalysts" citrate (6) oa A M F G omplex V Energy 3 ATP/ arvesting of these e Inner Membrane Matrix P TA, PD, FA oxidation, urea cycle ATP synthesis 1 ATP/FAD 1 GTP ~ 1 ATP I αkg oa 1 ATP per of oa oxidized ATP 1. PD 3 Pyruvate (P) The hemistry 3 N E1 E E3 Toxicity of As 3 3 Lipoic acid FAD oa Products a.) etyl oa b.) Reaction mechanism is strikingly similar to αkgd (below). asically, the pair of electrons move left to right across PD (E1 E E3) and reduce FAD FAD. Then, in a redoxchallenged last step, FAD gives its electrons to to yield. The is oxidized by the electron transfer chain (later.) itrate ynthase is stereospecific. oa attacks from top ( i ) face only. More detail on this later. laisen Reaction xaloacetate (A) ne micro-molar concentation very precious! oa oa itroyl oa Unstable! ΔG o = -31 KJ/mol arbanion oa Markers oa itrate () 17 D

2 A ession 10 from oa from A - works only on the bottom part of citrate (the "Pro-R" Arm) water removed and re-added I (Iso-citrate) ee next page on stereochemical specificity of onitase ( ) Isocitrate ID oxalosuccinate unstable (a β-keto acid) ID loss of is typically irreversible αketo Glutarate αkg looks like pyruvate with an acetate "decoration" αkgd very similar to PD 18 αketo Glutarate oa PLP αkgd Glutamic id (E) more later Label ( & ) becomes scrambled! ecause the molecule is symmetrical and D cannot tell the two ends apart. Malate Asp (D) oa uccinyl oa uccinyl oa synthetase P i oa GDP (ADP) GTP (ATP) uccinate FAD D FAD Fumarate Note trans isomer Fumarase Malate MD A -- Thio-ester attacked by phosphate -- Look at GAPD chemistry! -- ubstrate-level phosphorylation symmetrical compound ound to D -- which is embedded in mitochondrial inner membrane -- D also known as omplex II uccinate ylce starts again Next oa

3 Detail on tereochemical pecificity of onitase A The hydroxyl group always moves to the ProR arm and never to the Pro, even though they are chemically identical, because can distinguish the two arms (based on prochirality). (itrate) I (Iso-citrate) Pro Arm Pro Arm Pro R Arm Pro R Arm -- The stereochemistry defined by generates only one isomer - where the -, and fit in a specific way in three docking locations on. -- The -, and make contact with at three sites.

4 Anapleurotic Pathways A We know three Pathways -- look at Interactions -- Definition: anapleurotic "filling up" -- Pathways that maintain catalytic amounts of TA cycle intermediates - Today we'll add more detail to this network - tart with problem of how different life forms avoid running out of cytoplasmic ytoplasm Ala Mitochondrion G Glycolysis P PLP Asp P P PD oa A I Lipids (later) Important cannot enter mitochondrion / M F / αkg oa Glu ther stuff

5 MIT penourseware iological hemistry I Fall 013 For information about citing these materials or our Terms of Use, visit: