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1. THE CENTRAL IMPORTANCE OF AMPK, AMPK AS
A FUEL SENSOR,AMPK AS AN IMPORTANT
TARGET FOR EXERCISE AND DIABETIC
CONTROL DRUGS.
GROUP2 ,TEAM 4
JUNE 14,2016
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2. OUTLINE
 Definition of AMPK
 Central importance of AMPK
 Effect of AMPK on exercise
 AMPK as target for anti-diabetic drugs.
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3. AMPK
(5’ adenosine monophosphate-activated protein)
 Also known activated protein kinase.
 Is a an enzyme that plays a role in cellular energy homeostasis. It`s
master metabolic regulator
 It is a trimeric protein formed from 3 subunits
 It has catalytic α & regulatory two β and three γ sub units
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4. Isoforms of AMPK
 Each sub unit has its own iso-forms, with different tissue specificity
 The a subunit has α1 & a2 isoforms
 The B subunit has β1&β2 isoforms
 The y sub unit has γ1, γ 2 , γ 3 isoforms
 The a2 β2 γ1 predominates in skeletal muscle whereas in liver a1 β2 γ1
is abundant
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5. AMPK structure5

6. Contd…
 The γ sub unit has 4 cystathionine beta synthase(CBS) domains which gives
AMPK ability to detect the shift of AMP/ATP ratio
 These 4 domains form two binding site for AMP
 During the binding of AMP, y-sub unit undergoes conformational change
exposing catalytic a sub unit
 AMPK is activated when phosphorylation take place at Threonine-172 by AMPKK
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7. AMPK
Found almost everywhere.
 In organisms ranging from yeast to humans
 In a number of tissues like- liver, brain and skeletal
muscle.
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8. CENTRAL IMPORTANCE OF AMPK
 Acts a metabolic master switch regulator- maintaining energy
homeostasis.
 Acts a major cellular energy sensor, which can be attributed
to it`s sensitivity to AMP/ATP ratio
 Its activity increase when there ATP demand by cells
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9. AMPK AS A FUEL SENSOR
 Metabolic input to this sensor determine whether its protein
kinase activity take place.
 When cellular energy levels are high, as signalled by high
ATPS concentration ,AMPK becomes inactive.
 When cellular energy levels are depleted, as signalled by
high AMP concentration, AMPK becomes active.
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10. Activation
 AMPK is phosphorylated by at least 3 different AMPK kinases
1. by calmodulin-dependent kinase kinase (CaMkkB)
2. Serine-threonine kinases,LKB1
3. Transforming growth factor-B
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11. CONTD…
 Its activation by switch cells from active ATP consumption pathways
to active ATP production pathways.
 It inhibits of energy-consuming anabolic biosynthetic pathways like
Fatty acid and protein synthesis……
 And activates of ATP-producing catabolic pathways like fat acid and
glucose oxidation.
 These rapid events are called short-term regulatory processes but it
also exerts long term effects at gene expression and protein
synthesis
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12. Glucose sensor in the hypothalamus
Hypothalamic AMPK activity is increased during fasting when AMP
level is high and decreased during refeeding when the level of AMP
lowers
AMPK activation leads to increased food intake
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13. AMPK target key enzymes in energy
production and consumption
 Activation of AMPK leads to phosphorylation of many enzyme in
energy metabolism.
 AMPK effect on transcription factor also leads to diminished
expression of genes encoding biosynthetic enzymes and elevated
expression of catabolic genes.
 Enzymes involved in energy production are phosphorylated and
become activated so that they stimulate glycolysis.
e.g.PFK1
 Enzymes involved in energy consumption are phosphorylated and
become inactivated so that they inhibit glycogenesis.
e.g. Glycogen synthase, acetyl coA carboxylase etc..
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14. AMPK activity regulation is through
 direct activation by AMP (allosterically)
 Activation by other kinases (like upstream kinases)
 inhibition by protein phosphatases.
REGULATION OF AMPK14

15. Central role of AMPK in regulation of metabolism15

16. AMPK as target for exercise
 AMPK is activated by any stress that increases in AMP/ATP.
 This includes hypoxia, heart shock, exercises, and glucose
deprivation.
 The activation initiates signalling cascades that stimulate
changes in glucose, fatty acid metabolism and gene
expression.
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17. Cont`d
 Several groups have recently hypothesized that exercise
increases glucose uptake via an insulin-independent
mechanism mediated by the activation of AMP-activated
protein kinase (AMPK)
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18. Why is AMPK a target for anti
diabetic drugs
1. improve glycemic control in T2D subjects because activation of AMPK when
cellular energy is low provides an alternative pathway for the uptake of glucose.
2. AMPK activation can improve insulin sensitivity and metabolic health. Elevated
glucose production by the liver is a major cause of fasting hyperglycemia in T2D
and AMPK can control glucose production.
3. A common characteristic of T2D is high circulating lipid levels. In T2D patients
insulin release is defective so AMPK can regulate lipolysis.
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19. AMPK as target for exercise and diabetic
drugs
Type 2 diabetes is caused by
 Insulin resistance
 Defects of insulin secretion by β-cells.
 AMP-activated protein kinase (AMPK) is one of the probable target of major anti-diabetic
drugs,
 Metformin- Activated AMPK in hepatocytes.
 TZDs
 Salicylate
 Phenobarbital
 2-Deoxyglucose
Hormones
 insulin sensitizing adipokines (e.g., adiponectin).
 Leptin in skeletal muscle.
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20. METFORMIN(dimethyl biguanide)
 Is a derivative of biguanide found to be effective in lowering blood glucose in animals.
 Its sister drug phenoformin(phenetylbiguanide).
 Its major effect is known to be reduction of high hepatic glucose production in type 2 diabetics
 Metformin inhibit complex I of the respiration chain, suggesting that it might activate AMPK.
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21. Thiazolidinedione(TZD)
 Are representatives of another major class of anti-diabetic drug
piogliglitazone
rosiglitazone
troglitazone
 Have direct target activation of AMPK
 They activate AMPK both by a hormonal (adiponectin dependent mechanism) and by a cell
autonomous (adiponectin independent mechanism)
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22. 2-Deoxyglucose(2-DG)
 Taken up by a cell and converted to 2-deoxyglucose-6-phosphate by hexokinase
which is not metabolized beyond that point.
 It is inhibitor of glycolysis hence, it also activate AMPK in part by depleting ATP
due to is rapid and uncontrolled phosphorylation by hexokinase.
 It does not inhibit oxygen uptake.
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23. Salicylate
 Traditionally extracted from a willow bark.
 It is also produced by many plants as a hormone used in a defense response
triggered by infection by fungi and other pathogens.
 Acetyl Salicylate( ASA, trade name aspirin) is a derivative that is easier to take
orally than salicylate.
 ASA rapidly broken down to salicylate once it enters the circulation.
 Salicylate is not directly synthesized by humans.
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24. Phenobarbital
 It is a particularly effective inducer of cytochrome P450 enzymes that catalyze
oxidation of hydrophobic drugs.
 Induction of P450 enzyme by phenobarbital is mediated by AMPK.
 Activates AMPK , like biguanides and thiazolidinedione, because it is an inhibitor
of respiratory chain.
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25. Hormones that ellict anti-diabetic effect.
Leptin
 secreted by adipocytes
 Acts on the brain to regulate food intake and body weight.
 Leptin increases the AMP/ATP in skeletal muscle thus, activating AMPK.
Adiponectin
 Secreted by adipose tissue.
 Circulates at high concentration in the plasma.
 Activates AMPK through signalling.
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26. activated AMPK can induce food intake through its action in the
hypothalamus but will likely be undesirable for pharmaceutical targeting
of AMPK for the treatment of T2D and obesity.
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27. References
 AMPK signaling in metabolic regulation, ebook by yun Chau Long and Juleen R.
Zierath
 AMPK as a New Target for Antidiabetic Drugs, ebook by Arie Gruzman, Gali Babai,
and Shlomo Sasson
 en.wikipedia.org/wiki/AMP-activated_protein_kinase
 AMPK signaling:the fuel sensor and regulator pathway,
docs.abcam.com/pdf/cardiovascular/ampk_signaling.pdf
 AMPK: key sensor of fuel and energy status,
physiologyonline.physiology.org/content/21/1/48
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28. THANK YOU
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