1 METABOLISMO DE CARBOHIDRATOS 1(GLUCÓLISIS, CICLO DE LAS PENTOSAS, CICLO DE KREBS, CADENA RESPIRATORIA Y FOSFORILACIÓN OXIDATIVA, GLUCONEOGÉNESIS) MQ JGZ

2 GLUCÓLISIS Catabólica, en citoplasma. La primera parte consume ATP.La segunda parte produce equivalentes reductores y ATP a nivel de sustrato. Con excepción de tres reacciones todas son reversibles. MQ JGZ

3 Figure 11.2 Interactions between glycolysis and other metabolic pathways. The green colored boxes indicate intermediates involved in the pathway of glycolysis. Other boxes illustrate some of the metabolic interactions between glycolysis and other metabolic pathways in the cell. Not all of these pathways are active in the red cell which has limited biosynthetic capacity and lacks mitochondria. Glc-6-P, glucose-6-phosphate; Fru-6-P, fructose-6-phosphate; Fru-1,6-BP, fructose-1,6-bisphosphate. Downloaded from: StudentConsult (on 26 January :56 AM) © 2005 Elsevier

4 Figure 11. 3 The investment and splitting stages of glycolysisFigure 11.3 The investment and splitting stages of glycolysis. Note the consumption of ATP at the hexokinase and phosphofructokinase-1 reactions. Downloaded from: StudentConsult (on 26 January :56 AM) © 2005 Elsevier

5 Figure 11. 4 The yield stage of glycolysisFigure 11.4 The yield stage of glycolysis. Substrate-level phosphorylation reactions catalyzed by phosphoglycerate kinase and pyruvate kinase produce ATP, using the high-energy compounds, 1,3-bisphosphoglycerate and phosphoenolpyruvate, respectively. Note that the NADH produced during the glyceraldehyde-3-phosphate dehydrogenase reaction is converted back into NAD+ during the lactate dehydrogenase reaction, permitting continued glycolysis in the presence of only catalytic amounts of NAD+. © 2005 Elsevier

6 Figure 11.7 Allosteric regulation of phosphofructokinase-1 (PFK-1) by ATP. AMP is a potent activator of PFK-1 in the presence of ATP. Downloaded from: StudentConsult (on 31 January :00 PM) © 2005 Elsevier

7 Figure 11.8 Pathway for biosynthesis and degradation of 2,3-bisphosphoglycerate (2,3-BPG). BPG mutase catalyzes the conversion of 1,3-BPG into 2,3-BPG. The same enzyme has bisphosphoglycerate phosphatase activity, which hydrolyzes the 2-phosphate group, yielding 3-phosphoglycerate. Note that this pathway bypasses the phosphoglycerate kinase reaction, so that the overall yield of ATP per mol of glucose is decreased. Downloaded from: StudentConsult (on 31 January :00 PM) © 2005 Elsevier

8 PRODUCCIÓN DE LA GLUCÓLISISProducción neta: 2ATP, 2NADH+H+, 2 piruvatos (aeróbica) o 2ATP y 2 lactatos(anaeróbica) MQ JGZ

9 CICLO DE LAS PENTOSAS En tejidos con alta síntesis de ácidos grasos y esteroides, p. ej. mamas en lactancia, hígado, adiposo, corteza suprarrenal, tiroides, eritrocitos, testículos. MQ JGZ

10 2. formar ribosas para la síntesis de nucleótidos y ácidos nucleicos.CICLO DE LAS PENTOSAS Dos funciones: 1. formar NADPH para síntesis de ácidos grasos y esteroides, y regeneración de glutatión reducido. 2. formar ribosas para la síntesis de nucleótidos y ácidos nucleicos. MQ JGZ

11 CICLO DE LAS PENTOSAS Las enzimas están en el citosol.Usan NADP+ y no NAD+ como en la glucólisis. El principal producto es ribosa, como subproducto el CO2, no genera ATP. MQ JGZ

12 Figure 11. 9 The redox stage of the pentose phosphate pathwayFigure 11.9 The redox stage of the pentose phosphate pathway. A sequence of three enzymes forms 2 moles of NADPH per mole of Glc-6-P, which is converted into ribulose-5-phosphate, with evolution of CO2. Downloaded from: StudentConsult (on 31 January :00 PM) © 2005 Elsevier

13 Figure The interconversion stage of the pentose phosphate pathway. The carbon skeletons of three molecules of ribulose-5-phosphate are shuffled to form two molecules of Fru-6-P and one molecule of glyceraldehyde 3-phosphate. Downloaded from: StudentConsult (on 31 January :00 PM) © 2005 Elsevier

14 Figure 11.11 Glutathione. Structure of reduced glutathione (GSH) and oxidized glutathione (GSSG).Downloaded from: StudentConsult (on 31 January :00 PM) © 2005 Elsevier

15 Figure 11. 12 Antioxidant activities of glutathioneFigure Antioxidant activities of glutathione. GSH is the coenzyme for glutathione peroxidase which detoxifies hydrogen peroxide and organic (lipid) hydroperoxides. Hydrogen peroxide and lipid peroxides are formed spontaneously in the red cell, catalyzed by side reactions of heme iron during oxygen transport on hemoglobin (Chapter 35). Downloaded from: StudentConsult (on 31 January :00 PM) © 2005 Elsevier

16 REACCIÓN DE LA PIRUVATO DESHIDROGENASA (PDH)Piruvato entra a la mitocondria por simportador con H+. Luego viene la reacción de la PDH, que requiere varias coenzimas: tiamina (déficit en alcoholismo crónico), CoASH, NAD+. PDH es inhibida por NADH+H+, ATP, y activada por insulina. Se produce Acetil-CoA que luego entra al ciclo de Krebs. MQ JGZ

17 Figure 13. 3 Pyruvate is at the crossroads of metabolismFigure 13.3 Pyruvate is at the crossroads of metabolism. Pyruvate is readily formed from lactate or alanine. Acetyl-CoA and oxaloacetate are derived from pyruvate through the catalytic action of pyruvate dehydrogenase and pyruvate carboxylase, respectively. ADP, adenosine diphosphate. Downloaded from: StudentConsult (on 31 January :22 PM) © 2005 Elsevier

18 Figure 13. 12 Regulation of the pyruvate dehydrogenase complexFigure Regulation of the pyruvate dehydrogenase complex. The pyruvate dehydrogenase complex regulates the flux of pyruvate into the TCA cycle. NAD(H), ATP and acetyl CoA exert both allosteric and covalent control of enzyme activity. PDH, pyruvate dehydrogenase; TA, dihydrolipoyl transacetylase; DHLD, dihydrolipoamide dehydrogenase subunit.

19 CICLO DE KREBS Anfibólica.Transforma acetato (transportado por CoA) en CO2, H2O, con producción de NADH+H+, FADH2 y ATP. MQ JGZ

20 Figure 13. 1 Amphibolic nature of the TCA cycleFigure 13.1 Amphibolic nature of the TCA cycle. The TCA cycle provides energy and metabolites for cellular metabolism. Because of the catabolic and anabolic nature of the TCA cycle, it is described as amphibolic. FAD, flavin adenine dinucleotide; GDP, guanosine diphosphate; NADH, nicotinamide adenine dinucleotide; Pi, inorganic phosphate. Downloaded from: StudentConsult (on 31 January :22 PM) © 2005 Elsevier

21 Figure 13. 2 Metabolic sources of acetyl-CoAFigure 13.2 Metabolic sources of acetyl-CoA. Carbohydrates, lipids and amino acids are precursors of mitochondrial acetyl-CoA necessary for operation of the TCA cycle. Downloaded from: StudentConsult (on 31 January :22 PM) © 2005 Elsevier

22 Figure 13.7 Intermediates and enzymes of the TCA cycle.Downloaded from: StudentConsult (on 31 January :22 PM) © 2005 Elsevier

23 Figure 13. 8 Toxicity of fluorocitrate - a suicide substrateFigure 13.8 Toxicity of fluorocitrate - a suicide substrate. Fluorocitrate is a competitive inhibitor of aconitase. OAA, oxaloacetate. Downloaded from: StudentConsult (on 31 January :22 PM) © 2005 Elsevier

24 CADENA RESPIRATORIA Y FOSFORILACIÓN OXIDATIVAEs el acople entre la respiración (proceso oxidorreductor) y la síntesis de ATP. MQ JGZ

25 CADENA RESPIRATORIA Y FOSFORILACIÓN OXIDATIVA.El NADH de la glucólisis entra a la mitocondria: Hígado, riñón, corazón: lanzadera malato-oxalacetato (NADH). Cerebro y músculo: lanzadera de dihidroxiacetona fosfato-glicerol-3-P (FADH2). En la membrana interna mitocondrial: Hay transporte de equivalentes reductores (e-) Ocurre fosforilación oxidativa por una ATPasa (teoría quimiosmótica) MQ JGZ

26 MQ JGZ

27 CADENA RESPIATORIA Y FOSFORILACIÓN OXIDATIVAPRODUCCIÓN TOTAL VÍA METABÓLICA SUSTRATO PRODUCTOS GLUCÓLISIS AERÓBICA GLUCOSA 2 ATP, 2 NADH+H+, 2 PIRUVATO PDH PIRUVATO NADH+H+, ACETIL-CoA KREBS ACETIL-CoA 3 NADH+H+, 1 FADH2,1 ATP CADENA RESPIATORIA Y FOSFORILACIÓN OXIDATIVA NADH+H+ FADH2 3ATP 2ATP MQ JGZ

28 GLUCONEOGÉNESIS PRINCIPALES SUSTRATOS:LACTATO: CICLO DE CORI=LACTATO MUSCULAR A HÍGADO → PIRUVATO. GLICEROL: DE TAG. AMINO ÁCIDOS: PRINCIPALMENTE ALANINA EN MÚSCULO:GLUCOSA → PIRUVATO (TRANSAMINACIÓN) → ALANINA EN HÍGADO:ALANINA (TRANSAMINACIÓN) → PIRUVATO → GLUCOSA MQ JGZ

29 GLUCONEOGÉNESIS FUNCIONA CUANDO NO HAY SUFICIENTE GLUCOSA PARA SNC Y ERITROCITOS. SIEMPRE HAY REQUERIMIENTOS BASALES DE GLU. GLUCONEOGÉNESIS DEPURA PRODUCTOS METABÓLICOS MQ JGZ

30 GLUCONEOGÉNESIS ES LA GLUCÓLISIS A LA INVERSA EXCEPTO POR TRES REACCIONES IRREVERSIBLES: 1. PIRUVATO A PEP POR PIRUVATO CARBOXILASA (MIT) Y PEP CARBOXIQUINASA. 2. FRUCTOSA 1,6 BI-P A FRUCTOSA 6 P POR FRUCTOSA 1,6 BIFOSFATASA 3. GLU 6 P A GLU POR GLUCOSA 6 FOSFATASA MQ JGZ

31 Figure 12.8 Dotted lines: inactive during gluconeogenesis.MQ JGZ Downloaded from: StudentConsult (on 1 February :40 AM) © 2005 Elsevier

32 Figure 12. 9 Regulation of gluconeogenesisFigure 12.9 Regulation of gluconeogenesis. Gluconeogenesis is regulated by hepatic levels of Fru-2,6-BP and acetyl CoA. The upper part of the diagram focuses on the reciprocal regulation of Fru-1,6-BPase and PFK-1 by Fru-2,6-BP and the lower part on the reciprocal regulation of pyruvate dehydrogenase (PDH) and pyruvate carboxylase (PC) by acetyl CoA. MQ JGZ