Carbohydrate metabolism 3. Atip Likidlilid

Size: px

Start display at page:

Download "Carbohydrate metabolism 3. Atip Likidlilid"

Eugene Ramsey
5 years ago
Views:

1 Carbohydrate metabolism 3 Atip Likidlilid

2 Glycogenolysis muscle glycogen (1-2 % by weight) liver glycogen (6-10 % by weight)

3 Glycogen for energy storage > fat 1. Muscles cannot mobilize fat as rapid as glycogen. 2. Fatty acid residues of fat cannot be metabolized anaerobically. 3. Animals cannot convert fatty acid to glucose (lack of glyoxylate cycle) ; fat metabolism cannot maintain blood glucose.

4 Glyoxylate cycle

6 Glycogen breakdown - occurs in cytosol - requires 3 enzymatic actions

7 1. Glycogen phosphorylase (PLP) phosphorylase a, glycogen phosphorylase (pyridoxal phosphate) phosphorolysis from nonreducing end glycogen + Pi glycogen + G-1-P (n residues) (n-1 residues) leave 4 units from a branch point dextrin limit

8 2. Glycogen debranching enzyme (bifunctional or tandem enzyme) 4-α-glucanotransferase amylo-1,6-glucosidase 90 % of glycogen glucose residues = G-1-P 10 % of glycogen glucose residues = glucose

9 nonreducing end α-1,4 α-1,6 reducing end Pi glycogen phosphorylase P P G-1-P P P + glucanotransferase H 2 O amylo-1,6-glucosidase + glucose

10 3. Phosphoglucomutase phosphoglucomutase G-1-P G-6-P glycolysis (muscle) G-6-phosphatase G-1-P G-6-P glucose (liver)

11 Cascade regulation

12 epinephrine (muscle,liver) or glucagon (liver) adenylate cyclase (inactive) adenylate cyclase (active) insulin + phosphodiesterase ATP camp 5 -AMP protein kinase A (camp-dependent) (inactive) insulin + protein kinase A (active) phosphorylase kinase (inactive) * phosphorylase kinase (active)

13 phosphorylase kinase (inactive) phosphorylase b (inactive) insulin + * phosphorylase kinase (active) phosphorylase a (active) glycogen G-1-P * dephosphorylated by phosphoprotein phosphatase-1

14 ANABOLISM

15 Glycogenesis blood glucose cells

16 - occurs in cytosol glucose glucose hexokinase glucokinase glucose-6-p (muscle) glucose-6-p (liver) glucose-6-p phosphoglucomutase glucose-1-p glucose-1-p + UTP UDP-glucose pyrophosphorylase UDP-glucose + PPi

17 Glycogen synthesis

18 glycogenin + 6 UDP-glucose ( protein-tyrosine-glucosyltransferase ) glycogen primer + 11 UDP-glucose glycogen synthase α (1,4)-polyglucose chain + n UDP-glucose glycogen synthase + branching enzyme glycogen particle

19 glycogen primer (GP) + 11 UDP-glucose (core) glycogen synthase (non-reducing end) nonreducing end α-1,4 (for glycogen synthase) nonreducing end nonreducing end (for glycogen synthase) GP branching enzyme (transfer 7 units of glucose to C 6 position of first glucose) GP

20 Hormonal cascade regulation

21 epinephrine or glucagon inactive adenylate cyclase active adenylate cyclase insulin ATP camp 5 -AMP phosphorylase synthase (inactive) phosphorylase synthase (active) active protein kinase A glycogen synthase b (inactive) (D) glycogen synthase a (active) (I) phosphorylase b (inactive) phosphorylase a (active) glycogen phosphoprotein phosphatase-1 insulin

22 Insulin action

23 insulin α α insulin receptor β β membrane tyrosine kinase-p (autophosphorylation) insulin receptor substrate reversal of glucagonstimulated phosphorylation phosphorylation of proteins (phosphatase-1) other protein kinase other protein kinase-p induction and repression of specific genes stimulation of general protein synthesis stimulation of glucose transport

24 Regulation of glycogen storage in liver and muscle

25 Liver State Regulators Response Fasting CHO meal Blood : glucagon insulin Tissue : camp Blood : glucagon insulin glucose Tissue : camp glucose Glycogen degradation Glycogen synthesis Glycogen degradation Glycogen synthesis

26 Liver State Regulators Response Exercise and stress Blood : Tissue : epinephrine camp Ca 2+ -calmodulin Glycogen degradation Glycogen synthesis

27 Muscle State Regulators Response Fasting (rest) Blood : insulin Glucose transport Glycogen synthesis CHO meal (rest) Blood : insulin Glucose transport Glycogen synthesis

28 Muscle State Regulators Response Exercise Blood : epinephrine Tissue : camp Ca 2+ -calmodulin Glycogen degradation Glycolysis Glycogen synthesis

29 Gluconeogenesis occurs in liver, kidney and intestine using noncarbohydrate precursors glycolysis products : lactate, pyruvate TCA cycle intermediates carbon skeletons of amino acids (glucogenic amino acids) except leucine, lysine acetyl CoA (ketogenic amino acids) all of these substances except glycerol must be converted to oxaloacetate reversible reaction of glycolysis except 3 reactions

30 Ala,Cys,Gly,Ser,Thr,Trp lactate* pyruvate* glucose gluconeogenesis Phe,Tyr Asp,Asn malate fumarate succinate succinyl CoA Iso,Met,Val oxaloacetate citrate α-ketoglutarate acetyl CoA isocitrate Arg,Glu,Gln, His,Pro

31 bypass reaction of glycolysis, rate limiting enzymes cytosol matrix glucokinase NAD + NADH+H + FPK-1 pyruvate kinase glucose G-6-P F-6-P F-1,6-bis P Gly-3-P 1,3-bis P Gly PEP Pi pyruvate PEP carboxykinase (GTP) OAA 3 G-6- P ase 2 F-1,6-bis P ase-1 phosphoglycerate kinase (ATP) 1 biotin pyruvate carboxylase (ATP)

32 - pyruvate carboxylase occurred in mitochondrial matrix - PEP carboxykinase occurred in mitochondrial matrix or cytosol Regulation of gluconeogenesis - pyruvate carboxylase is allosteric enzyme - acetyl CoA activates pyruvate carboxylase and inhibits pyruvate kinase Gluconeogenesis requires 6 phosphoanhydride bonds - pyruvate carboxylase consumes 2 ATP molecules - PEP carboxykinase consumes 2 GTP molecules - phosphoglycerate kinase consumes 2 ATP molecules

33 muscle LDH lactate pyruvate mitochondria cytosolic transaminase Py carboxylase malate DH malate DH alanine pyruvate pyruvate OAA malate malate OAA GTP CO 2 ADP ATP +Pi NADH+H + Py carboxylase pyruvate OAA NAD + mt PEP carboxykinase PEP NAD + NADH+H + cytosolic PEP carboxykinase CO 2 GDP PEP NAD + NADH+H + CO 2 ATP ADP +Pi GTP cytosol

34 1 Conversion of pyruvate into PEP pyruvate + ATP + GTP + CO 2 PEP + ADP + GDP + 2 Pi ΔG = -25 kj / mol

35 2 Conversion of F-1,6-bisP into F-6-P F-1,6-bis P + H 2 O F-6-P + Pi ΔG = kj / mol

36 3 Conversion of G-6-P into free glucose G-6-P + H 2 O glucose + Pi ΔG = kj / mol

37 Regulation of gluconeogenesis and glycolysis in liver

38 A. glycolytic enzymes mechanism pyruvate kinase + F-1,6-P - ATP,alanine - by phosphorylation * phosphofructokinase-1 + F-2,6-bisP (insulin), AMP glucokinase high K m for glucose induced by insulin * + glucagon,epinephrine camp protein kinase A

39 B. glucogenic enzymes mechanism pyruvate carboxylase + acetyl CoA PEP carboxykinase induced by glucagon, epinephrine,glucocorticoids fructose-1,6- bisphosphatase suppressed by insulin induced during fasting inhibited by F-2,6-bisP,AMP glucose-6-phosphatase induced during fasting

40 application Industrial application - insecticide, rodenticide - toothpaste

41 Medical application - acarbose (glucabay) จ ดเป น glucosidase inhibitor ย บย งเอนไซม disaccharidase และ pancreatic amylase - tolrestat และ epalrestat ย บย งเอนไซม sorbitol (aldose) reductase (p.234) ป องก นการเก ด cataract - metformin : กระต น glucose uptake by glucose transporter : กระต น tyrosine kinase activity of insulin receptor : ย บย ง gluconeogenesis

42 - 3-mercaptopicolinate และ hydrazine ย บย งเอนไซม PEP carboxykinase in gluconeogenesis - sulfonylurea เช น glimepiride, glycopyramide, gliquidone, glibenclamide (glyburide),tolazamide etc. กระต นการหล ง insulin โดยจ บก บ ATP-dependent K + channel ท าให K + ออกจากเซลล ไม ได จ งไปเป ด Ca 2+ channel ท าให Ca 2+ เข าส เซลล ซ ง Ca 2+ จะไปกระต นการหล ง insulin - dichloroacetate กระต น PDH ในห วใจจ งกระต น TCA cycle ใช ร กษาโรค Ischaemic heart disease

43 Benefit - lactase deficiency : lactose intolerance - pyruvate kinase deficiency : chronic hemolytic anemia - G-6-PDH deficiency: acute hemolytic anemia - advanced glycation end product (p.258) เช น HbA 1c ม ประโยชน ในการต ดตาม long-term serum glucose level ใน ผ ป วยเบาหวาน เพราะเม ดเล อดแดงม อาย ประมาณ 4 เด อน - deficiency of enzyme in glycogenolysis :glycogen storage disease (glycogenosis) (p.246)

Link download full of Test Bank for Fundamentals of Biochemistry 4th Edition by Voet

Link download full of Test Bank for Fundamentals of Biochemistry 4th Edition by Voet http://testbankair.com/download/test-bank-for-fundamentals-ofbiochemistry-4th-edition-by-voet/ Chapter 16: Glycogen