biochemistry of MSS prepared by Fikadu Seyoum Tola. This ppt essentially discuss about collegen biosnthesis, defect and muscle energy metabolism with its regulations.
biochemistry of MSS prepared by Fikadu Seyoum Tola. This ppt essentially discuss about collegen biosnthesis, defect and muscle energy metabolism with its regulations.
Similar to biochemistry of MSS prepared by Fikadu Seyoum Tola. This ppt essentially discuss about collegen biosnthesis, defect and muscle energy metabolism with its regulations.
Similar to biochemistry of MSS prepared by Fikadu Seyoum Tola. This ppt essentially discuss about collegen biosnthesis, defect and muscle energy metabolism with its regulations. (20)
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biochemistry of MSS prepared by Fikadu Seyoum Tola. This ppt essentially discuss about collegen biosnthesis, defect and muscle energy metabolism with its regulations.
2. Brain storm
1. How glucose inters to the cell for metabolism
2. What is metabolism
3. What is metabolic pathway
4. What is glycolysis
5. What is the d/c b/n Anaerobic and Aerobic glycolysis
6. How many ATP produced by glycolysis
7. Which cell is completely depend on glycolysis to gain energy
8. Which organ use the most daily required glucose/energy?
3. Introduction to carbohydrate
ďCHO is chemically defined as aldehyde or ketone derivative of higher polyhydric
alcohol.
ďCarbohydrates are polyhydroxy containing molecules in its structure.
ďCHO is the most abundant organic molecules in the nature.
ďThe name of carbohydrate came from hydrates of carbon.
ďThe empiric formula for many simpler carbohydrates is (CH2O)n, where n >3.
4. Major function of carbohydrate
ďMajor energy source of most organism
ďStorage form of energy in the body
ďStructural components of cell wall, exoskeleton and, cell membrane
ďPrecursors of many others compounds in cell
5. Carbohydrate classification
1. Based on the number of sugar units
ďMonosaccharides= simple sugar that cannot hydrolyzed further. General formula : CnH2nOn
ďDisaccharides=Yields two molecules of the same or different molecules of monosaccharide on
hydrolysis. General formula : Cn(H2O)n-1
ďOligosaccharides=Those sugars which yield 3 to 10 monosaccharide units on hydrolysis, e.g.
Maltotriose.
ďPolysaccharides=above ten monosaccharides.
8. CHO absorption
⢠All monosaccharides, are completely absorbed from the small intestine.
⢠Some disaccharides, which escape digestion, may enter the cells lining
intestinal lumen may be by pinocytosis; and are hydrolyzed within these
cells
⢠No carbohydrates higher than the monosaccharides can be absorbed
directly into the bloodstream in normal health.
⢠If they administered parenterally, they are eliminated as foreign bodies.
9. Mechanism of sugar absorption
1. Active transport Mechanisms:
ďąGlucose and galactose are absorbed actively and it requires energy.
ďąSodium dependent sugar carrier-protein is called sodium-glucose co-transporter.
ďąSodium binding changes the conformation of the protein molecule, enabling the binding of
glucose to take place and thus the absorption to occur
2. Facilitated transport:
ďą Fructose and mannose is absorbed by facilitated transport
3. Simple passive diffusion:
ďą L-form of glucose and galactose, pentose sugars
10. Active transport
⢠It has two binding sites one for sodium and another for the glucose.
⢠It is sodium-dependent and energy-dependent.
12. Facilitated Transport Vs Active Transport
Similarities
ďBoth appear to involve carrier proteins.
ďBoth show specificity.
ďCarrierâ is saturable so it has maximum
rate of transport.
ďStructurally similar competitive
inhibitors block transport.
Differences
ďFacilitated transport can act bi-
directionally,
ď Active transport is unidirectional.
ďActive transport occur against chemical
gradient and hence requires energy.
ďFacilitated transport does not require
energy
13. Rate of monosaccharide absorption
⢠Cori studied the rate of absorption of different sugars from small intestine in rat
⢠The above study proves that glucose and galactose are absorbed very fast; fructose and
mannose intermediate rate and the pentoses are absorbed slowly
15. How glucose inters into the cell
⢠Since glucose is polar and hydrophilic molecule it cannot diffuse directly to the
cell
⢠There are a transport mechanism through which glucose get into the cells.
Transport mechanism
Na-independent facilitated diffusion Na-dependent glucose transport
They are designated GLUT-1 to GLUT-14 SGLT-1
No energy requiring, down conc. Energy is required
They are facilitated diffusion Move against conc.gradient
16. Glucose transporter specialization function
⢠In facilitated diffusion, glucose movement follows a concentration gradient (from a high glucose
concentration to a lower one.
⢠However, GLUT-2, which is found in the liver and kidney, can transport glucose into these cells
when blood glucose levels are high,
⢠It also transport glucose from the cells to the blood when blood glucose levels are low
18. Fates of Glucose in the cell
What are the four(4) major fate of glucose?
1.To synthesize large polymers like glycogen, starch, cellulose
2.Metabolized to three carbon pyruvate and other intermediate through
glycolysis
3.To oxidized via PPP to yield ribose-5-phosphate and NADPH
4.To yield extracellular matrix and cell wall synthesis
20. Introduction to glucose metabolism
⢠Glucose is the preferred source of energy for most of the body tissues.
⢠When the glucose metabolism is deranged, life threatening conditions may occur.
⢠Normal fasting plasma glucose level is 70 to 110mg/dL.
⢠After a heavy carbohydrate meal, it might reach up to 150 mg/dL
⢠Brain use approximately 120g/day glucose
21. What is metabolism
⢠The sum of all chemical transformation that occur inside the cell is called metabolism
⢠Metabolism can be catabolism or anabolism
⢠A series of reaction catalyzed by multienzyme sequence in which the product of one reaction
become the substrate for the next reaction is called metabolic pathway
22. Glycolysis
ďśThe word glycolysis derived from Greek word (glykys, âsweetâ or âsugar,â and lysis,
âsplittingâ).
ďśGlycolysis is the metabolic pathway through which glucose molecule is degraded in
series of enzyme-catalyzed reaction to yield 2 molecules of three carbon cpd called
pyruvate.
ďśGlucose is not only an excellent source of fuel, but also provide intermediate metabolites
ďAmino acid
ď Fatty acid
ď Nucleic acid, and
ď Coenzymes
23. Phases of glycolysis
⢠Glycolysis has 10 sequential enzymatic reaction that can be described by two major phases
1.Preparatory phase(energy investment)= 2ATP is consumed, phosphorylated intermediates are
produced.
25. Steps of glycolysis
Step-1 phosphorylation of glucose
ďPhosphorylated sugar molecules do not readily penetrate cell membranes, why?
1. Because there are no specific transmembrane carriers for these compounds,
2. They are too polar to diffuse through the cell membrane
ďTherefore, phosphorylation is the effective process to traps the sugar as cytosolic
glucose-6-phosphate
26. Step-2 Isomerization of glucose 6-phosphate
⢠Catalyzed by posho-hexose isomerase.
⢠The reaction is readily
oreversible and is
onot a rate-limiting or
onot committed step.
27. Step-3 Phosphorylation of fructose 6-phosphate
ďśThe 2nd phosphorylation reaction catalyzed by phosphofructokinase-1(PFK-1)
oIs the control point
oRate-limiting and
ocommitted step of glycolysis
oPFK-1 is allosterically regulated enz.
ďśPFK-2 produce F2,6-bisphosphate from F-6-P
ďśF 2,6-bp is activator of PFK-1 and inhibitor of phosphatase
28. Step-4 splitting of F 1,6 bisphosphate
⢠The reaction is catalyzed by Aldolase enzyme.
⢠Yield two different triose phosphates, glyceraldehyde 3-phosphate(aldose), and
dihydroxyacetone phosphate(a ketose)
⢠The reaction is reversible
29. Step-5 interconversion of triose
⢠Dihydroxyacetone phosphate must be isomerized to glyceraldehyde 3-phosphate
⢠This isomerization results in the net production of 2 molecules of glyceraldehyde
3-phosphate
30. Step-6 Oxidation of glyceraldehyde 3-phosphate
ďThis is the 1st oxidative-reduction reaction in glycolysis
ďThe aldehyde group of glyceraldehyde 3-phosphate is oxidized to 1,3-bisphosphoglycerate by
glyceraldehyde 3-phosphate dehydrogenase
ďNB: Arsenic poison inhibit this pass way by competing with inorganic phosphate as a substrate for
glyceraldehyde 3-phosphate dehydrogenase,
ďThen it forming a complex (1-arseno-3-phosphoglycerate) that spontaneously hydrolyzes to form
3-phosphoglycerate and bypass 1,3-bisphosphoglycerate formation and cause energy deprivation.
31. Step-7 Synthesis of 3-phosphoglycerate producing ATP
⢠This reaction is catalyzed by phosphoglycerate kinase
⢠This kinase reaction replaces the two ATP molecules consumed by preparatory
phase.
⢠This is an example of substrate-level phosphorylation
32. Step-8 Shift of the phosphate group from carbon 3 to carbon 2
⢠The shift of the phosphate group from carbon 3 to carbon 2 of phosphoglycerate
⢠Catalyzed by phosphoglycerate mutase
33. Step-9 Dehydration of 2-phosphoglycerate
ďś Fluoride inhibit enolase
ďś Sodium fluoride is used along with K-oxalate for collection of blood for glucose estimation.
ďś If K-oxalate is used alone, then in vitro glycolysis will reduce the glucose value in the sample.
ďś Functions of Fluoride
ďś Inhibits in vitro glycolysis by inhibiting enzyme enolase
ďś Also acts as anticoagulant, and an antiseptic
34. Step-10 Formation of pyruvate
⢠The conversion of PEP to pyruvate is catalyzed by pyruvate kinase
⢠This is another example of substrate-level phosphorylation
37. Comparison of aerobic and anaerobic glycolysis
B. In Glycolysisâin Absence of O2 (Anaerobic
Phase)
ď In absence of O2, reoxidation of NADH at
glyceraldehyde- 3-P-dehydrogenase stage cannot
take place in electron-transport chain.
ď But the cells have limited coenzyme. Hence to
continue the glycolytic cycle NADH must be
oxidized to NAD+.
ď This is achieved by reoxidation of NADH by
ď conversion of pyruvate to lactate (without
producing ATP) by the enzyme lactate
dehydrogenase.
ď In anaerobic phase per molecule of glucose
oxidation
ď 4 â 2 = 2 ATP will be produced.
40. Students are expected to know
1. What is glycogenesis and glycogenolysis
2. Where do glycogenesis and glycogenolysis take place(organ and organelles)
3. When do glycogenesis and glycogenolysis take place
4. How many gram of glycogen stored in liver and muscle
5. Why do glycogenesis and glycogenolysis take place
6. What are the steps of glycogenesis and glycogenolysis take place
7. What are the enzymes involve in glycogenesis and glycogenolysis take place
42. Glycogen metabolism
ďąThe constant source of glucose supply is absolutely required for cells.
ďąB/c glucose is the preferred energy source for brain and absolute source for mature
RBC.
The three source of blood glucose are
1. dietary intake of glucose,
2. glycogen degradation and
3. gluconeogenesis
43. Cont.,,,,
ďąDietary intake of glucose in the form of complex CHO is sporadic and not
reliable source of glucose.
ďąGluconeogenesis have sustainability but slowly response to low glucose.
ďąDue to this our body has developed mechanisms for storing a supply of glucose in
a rapidly mobilizable form called glycogen
44. Where do glycogen synthesis take place?
ďśThe major site for store of glycogen in the body is skeletal muscle and liver.
ďśMuscle glycogen used to provide energy to muscle during exercise, not use for
other cells.
ďśLiver glycogen is to maintain blood glucose particularly during early fasting.
ďś400g of glycogen stored in muscle and account 2% of muscle fresh weight
ďśwhereas 100g of glycogen store in liver and account 10% of liver weight.
ďśIn glycogen storage disease the amount of store is high in both muscle and liver.
45. Glycogen
⢠Glycogen is a multibranched polysaccharide of glucose that serves as a form of
energy storage in animals, fungi, and bacteria.
46. Glycogen structure
Picture taken from Lippincott illustrated 4th edition. Branched structure of glycogen, showing
Îą(1â4) and (1â6) linkages
47. Where is exact glycogen storage in cell
⢠Glycogen molecules exist in cytoplasmic granules associated with its degradatory
and synthetic enzymes.
⢠During early fasting liver glycogen depleted muscle glycogen depleted after
prolonged fasting, why??????
48. 1. Glycogen synthesis
o Glycogen synthesis is called glycogenesis
o Glycogen synthesis require primer for starting synthesis
o Primer is usually glycogen fragment or protein called glycogenin.
o Glycogenin elongated with a few UDP-glucose until glycogen synthase become
active by the process called autoglucosylation.
49. Steps in glycogenesis
Primer required.
ďśThe glycogen primer is formed by autoglucosylation of glycogenin.
ďśGlycogenin is a dimeric protein, the monomers glycosylating each other using UDP-glucose till
seven glucose units are added.
Step-1 Glucose activation step
⢠First G-6-P is converted to G-1-P by phosphoglucomutase enzyme.
.
50. Step in glycogenesis cont.âŚ
Step-1 glucose activation. G-1-P + UTP------UDP-Glucose + PPi by UDP-glucose
pyro phosphorylase
Step-2 Elongation of glycogen by glycogen synthase.
51. Glycogenesis
Step-3 formation of branch/branching
ďThe amylo-Îą(1â4) â Îą(1â6)-glucotransferase enzyme first cut 8 glucosyl
residues from the long glycogen.
ď Then it form branch with new nonreducing end.
ďThen after, elongation of branch will continues by glycogen synthase.
53. Glycogenesis
Adopted from Textbook of biochemistry for medical student
The enzyme amylo- 1, 4â1, 6-transglucosidase
(branching enzyme) forms the alpha-1, 6 linkage
54. 2. Glycogen degradation (glycogenolysis)
⢠Glycogen degradation is the mobilization of stored glucose in liver and muscle.
⢠It is not the reverse of glycogen synthesis as it involve different enzyme.
Step-1 shortening of the long glucose by glycogen phosphorylase
⢠Glycogen phosphorylase use pyrophosphate(PLP) as coenzyme and cleave 1-4
bond until 4 glucosyl residues remain before branch of 1-6.
⢠This short structure called limit dextrin.
55. Glycogenolysis
Step-2 branch removing/debranching
⢠The three glucose before branch is removed out and attached to another
nonreducing end by amylo-Îą(1â4) â Îą(1â4) glucotransferase(4:4 transferase).
⢠The remaining branching glucosyl residue removed by amylo-Îą(1â6) glucosidase
to free glucose.
⢠These two enzyme called debranching
58. Glycogenolysis in liver maintain blood glucose
⢠In the liver, glucose 6-phosphate is translocated into the endoplasmic reticulum
(ER) by glucose 6-phosphate translocase.
⢠There it is converted to glucose by glucose 6-phosphatase.
⢠The resulting glucose is then transported out of the ER to the cytosol by GLUT-7.
⢠Hepatocytes release glycogen-derived glucose into the blood to help maintain
blood glucose
⢠This process used to maintain blood glucose until the gluconeogenic pathway is
actively producing glucose.
59. Muscle glycogenolysis
⢠Unlike to liver muscle glycogen muscle glycogen do not use to maintain blood
glucose
⢠Because muscle has no enzyme to convert Glucose-6-phosphate to free glucose
⢠Muscle derived glucose used as energy source for muscle itself
⢠Muscle glycogenolysis is the major energy source for muscle during strenuous
exercise
61. Glycogen metabolism regulation
ďśIn order to maintain blood glucose, glycogen synthesis and degradation should be tightly regulated
ďśGlycogen synthesis in liver accelerated during well fed and degradation accelerated during fasting.
ďśIn muscle degradation accelerated during exercise and synthesis after exercise/at rest.
1.Allosteric regulation
ďśBoth glycogen synthase and glycogen phosphorylase regulated by the metabolites and energy
level of the cell
ďśThe availability of substrate like G-6-P and high energy(ATP) allosterically activate glycogen
synthase enzyme and inhibit glycogen phosphorylase
62. Glycogen metabolism regulation cont.âŚ
Taken from Lippincott illustrated 4th ed. Allosteric regulation of glycogen synthesis and degradation.
63. 2. Hormonal regulation of glycogen metabolism
ďHormone like glucagon and catecholamine release during fasting bind to their
specific membrane receptor.
ďWhen they bind they activate receptor and then G-couple receptor finally cAMP
increase
ďcAMP activate cAMP-dependent protein kinase through binding to its R-subunit
ďActivated cAMP-dependent protein kinase phosphorylate glycogen
phosphorylase(inactive-b-form) to active-a form.
65. 3. Glycogen degradation activation in muscle by Ca++
ď§ During muscle contraction energy is needed as ATP for the muscle cells
ď§ This energy is supplied by degradation of stored glycogen by muscle. How?
ď§ Nerve impulse cause muscle membrane depolarization that cause the release of
Ca++ from muscle sarcoplasm reticulum to cytoplasm of muscle.
ď§ The released muscle bind to calmodulin(4Ca2+-calmodulin complex) formed.
ď§ This complex bind to protein kinase in cytoplasm w/c is Camp-dependent kinase.
66. Muscle glycogen phosphorylase regulation by Ca++
⢠Activated protein kinase phosphorylate glycogen phosphorylase
⢠Then, muscle glycogen breakdown enhanced and G-6-P for ATP released
⢠When muscle relax released Ca++ returned to sarcoplasmic reticulum and kinase become inactive
.