Gluconeogenesis, glycogenesis, regulation Flashcards

Question

Which substances regulate the activity of PFK 1?

Answer 1

_allosteric inhibitors:_ * **ATP, FAs**: much energy in cell * **citrate** _allosteric activators:_ * **AMP** * **F2,6BP**, most important regulator of glycolysis

Answer 2

**increased rate of glycolysis during hypoxia/anoxia to compensate "missing" ATP production by oxidative phosphorylation** → ↓ [O₂] → ↑ [AMP] → activation of PFK 1 (rate-limiting) important for survival of tissues during hypoxia (e.g. after vascular obstruction)

Answer 3

* **inhibits F1,6BPase** * **activates PFK 1** ****⇒ **↑** [F1,6BP] = all. activator of pyruvate kinase → glycolysis

Answer 4

_tandem (= bifunctional) enzyme **PFK2/FBPase2**_ has 2 activities * **PFK2**: F6P → F2,6BP * **FBPase2**: F2,6BP → F6P

Answer 5

_activities are dependent on **de-/phosphorylation**_ controlled by hormone status in response to blood glucose levels * _catecholamines/glucagon:_ ↑ cAMP → PKA → **phosphorylation** → **FBPase2 activity** ⇒ F6P generated, used for gluconeogenesis * _insulin_ → protein phosphatase 1 → **dephosphorylation** → **PFK2 activity** ⇒ F2,6BP generated, activates glycolysis

Answer 6

* _in heart:_ **phosphorylation → PFK2 activity** ⇒ catecholamines incr. rate of glycolysis to cover for E requirements * _in sk. muscle:_ **no phosphorylation**, but catecholamines incr. F2,6BP due to ↑ [glucose]

Answer 7

in flying mm. of bumblebees: **PFK 1 and F1,6BPase active** → excessive ATP generation, resulting in thermogenesis _BUT:_ **permits very rapid incr. in rate of glycolysis,** if necessary for mm. contraction

Answer 8

_2 isoenzymes_ * _**PK-L** in **L**iver_, allosterically and covalently modified in response to hormones (otherwise unregulated production of pyruvate = futile cycle) * _**PK-M** in sk. **M**uscle_, _not regulated_ b/c no gluconeogenesis

Answer 9

* _activated_ by: **F1,6P** (feedforward) → glycolysis/E generation * _inhibited_ by: → gluconeogenesis * **ATP** (product inhibition) * **Ala**

Answer 10

* _activated_ by **dephosphorylation**: insulin * _inactivated_ by **phosphorylation**: glucagon

Answer 11

_induced by_ → gluconeogenesis * **glucocorticoids** * **glucagon** * **retinoids** _repressed by_ → glycolysis + glycogenesis * __**insulin**

Answer 12

* **in liver**: maintenance of blood glucose level * **in skeletal mm.**: provides glucose during exercise glycogen granule in the core, main chain w/ _α1,4-glycosidic linkages_, branches w/ _1,6-glycosidic linkages_ ⇒ **free, non-reducing ends**

Answer 13

**conversion of glucose to UDP-glucose** 1. _**phosphoglucomutase**:_ G6P ⇔ G1P 2. _**UDP-glucose pyrophosphorylase**:_ G1P + UTP → UDP-glucose + _PP_i_ _{β and γ-phosphate of UTP → pyrophosphate}

Answer 14

**DIPF** = diisopropylfuorophosphate → no conversion of G6P to G1P

Answer 15

**_glycogen synthase_** binds UDP-glucose to non-reducing ends of either * preexisting glycogen chain, or * glycogenin forming α 1,4-glycosidic linkages

Answer 16

**protein** forms the "primer" of glycogenesis → at core of glycogen granule ⇒ amount of glycogenin determines the cellular glycogen content (since primer for glycogen molecule)

Answer 17

**_glycosyl 4,6-transferase_** = branching enzyme when main glycogen chain at least consisting of 11 glucose units, part of chain transferred → α 1,6 branch points formed ⇒ incr. solubility, more non-reducing terminal residues incr. rate of metabolism

Answer 18

G6P + ATP + glycogen (n) + H₂0 ↓ glycogen (n+1) + ADP + 2P_i

Answer 19

**_phosphorylation_** by **glycogen phosphorylase** (rather than hydrolysis) → even possible under _anaerobic conditions_ (*ex*: exercise) **glycogen (n) + P_i→ G1P + glyogen (n-1)**

Answer 20

**_glycogen phosphorylase_** 2 subunits w/ **PLP** at catalytic site (prosthetic group) ⇒ acting as _acid-base catalyst_ to cleave α1,4-glycosidic bonds in glycogen (until 4 glucose residues remaining on either side of α1,6 branch)

Answer 21

**_debranching enzyme_** = 2 diff. catalytic sites 1. **glucan transferase**: transfers trisaccharide to α 1-4 main chain 2. **α 1,6-glycosidase:** _hydrolyzes_ 1,6 linkage → _free_ glucose formed

Answer 22

* _glycogenosis type Ia:_ **G6Pase** **defect** * _glycogenosis type Ib:_ **G6P transporter mutation** ⇒ G6P accumulates in liver

Answer 23

⇒ G6P accumulates in liver * causes **↑[G1P]** → inhibition of glycogenolysis → _hepatomegaly_ * no glucose export → _hypoglycemia_, ketosis, _hyperuricemia, hyperlipemia_

Answer 24

**deficiency of muscle glycogen phosphorylase** * poor exercise tolerance * muscle glycogen abnormally high (2-4%) * blood lactate very low after exercise

Answer 25

* **phosphorylase:** active at low [glucose] → glycogenolysis * **glycogen synthase:** active at high [glucose] → glycogenesis

Answer 26

isoenzymes in sk. mm, and liver _regulatory mechanisms:_ * **allosterically:** * inactive T state * active R state * **covalently mod.:** * ****phosphorylated active phosphorylase a * dephosphorylated inactive phosphorylase b ⇒ phosphorylase a mainly in R state, b mainly in T state

Answer 27

**_phosphorylase b_** ⇒ regulated by energy state of muscle cell _activation_ **→** glycogenolysis * allosterically by **AMP** → R state _inactivation_ * allosterically by **ATP, G6P** → stabilized T state

Answer 28

**glucose sensor function** b/c glucose is only regulator of liver's glycogen phosphorylase ⇒ high [glucose] causes stabilization of T state

Answer 29

_**catecholamines , glucagon** (only in liver!!)_ 1. binds to receptor → activation of **adenylate cyclase**: ATP to cAMP **→** PKA 2. PKA phosphorylates **phosphorylase kinase b to a** 3. phosphorylase kinase a phosphorylates **phosphorylase b to a** → glycogenolysis

Answer 30

_hexadecamer_ = 4 α, β, γ, δ subunits → δ subunits = **calmodulin**, can bind Ca²⁺ if **Ca²⁺ binds, activation** independently of phosphorylation by PKA _{(esp. important during mm. contraction to provide E supply by glycogenolysis)}

Answer 31

**allosterically + covalently modified** _BUT:_ reciprocal regulation to glycogen phosphorylase * dephosphorylated active form * phosphorylated inactive form has _9 phosphorylation sites_ → fine adjustment of activity

Answer 32

NOTE: **glycogensynthase kinase 3** esp. important _{inactivated by insulin}

Answer 33

**G6P** ⇒ activates glycogen synthase even if phosphorylated important when rate of glycogenesis should be increased very rapidly in response to insulin

Answer 34

**_protein phosphatase 1_** (PP1) catalytic subunit + regulatory tissue specific subunit (G subunit): association → activation * dephosphorylates _glycogen synthase_ → activation ⇒ glycogenesis * dephosphorylates _phosphorlyase kinase a_ and _phosphorylase a_ → inactivation ⇒ ↓ glycogenolysis

Answer 35

* **activates phosphodiesterase → ↓** cAMP → inactivated PKA * **activates insulin-sensitive PK** → phosphorylation of G subunit → associates with catalytic subunit of PP1 → dephosphorylates glycogen synthase/phosphorylase kinase a/phosphorylase a

Answer 36

**in response to cAMP** → activates PKA, then 2 mechanisms of inactivation * phosphorylates inhibitor so it can bind to PP1 * phosphorylates catalytic subunit, dissociates from G subunit _{in skeletal muscle}

Answer 37

activated in response to **catecholamines, glucagon** via cAMP levels * phosphorylates phosphorylase kinase = **active** * phosphorylates synthase = **inactive** * phosphorylates PP1 = **less active** * phosphorylates inhibitor of PP1 = **inactive** PP1 * phosphorylates PFK2/FBPase2 = eff. depends on tissue type

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Gluconeogenesis, glycogenesis, regulation Flashcards

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