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Medical Biochemistry and Pathophysiology > Week 2A: Signal transduction pathways, gluconeogenesis, oxidative phosphorylation 1+2 > Flashcards

Week 2A: Signal transduction pathways, gluconeogenesis, oxidative phosphorylation 1+2 Flashcards

HC07-10

1
Q

Signal transduction principles

A

-Primary signals like hormones which bind receptor
-Second messengers: signal transduction intracellular
-Activation of effectors like enzymes
-Termination of the signal

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2
Q

Receptor for epinephrine

A

beta-adrenergic receptor

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3
Q

Reaction EGF to EGF receptor

A

Expression of growth promoting genes > wound healing

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4
Q

Between which steps in signal transduction is amplification performedn

A

Between reception and transduction

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5
Q

Chemical signaling types

A

-Autocrine
-Across gap junctions
-Paracrine
-Endocrine (through blood)

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6
Q

Which cells respond directly to increased glucose levels?

A

Pancreatic islet cells

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7
Q

Adrenaline/ epinephrine response

A

Epinephrine + beta-adrenergic receptor (7TM) > fight or flight response: energy store mobilization

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8
Q

Release insulin effect on glucagon

A

Beta cells contain ready to go granules of insulin before the signal (secretion upon glucose influx)
> insulin binds to pancreatic alpha cells to inhibit glucagon secretion

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9
Q

Beta cell insulin secretion pathway

A
  • Carbohydrate rich meal > rise blood glucose > release insulin beta cells
    1. Glucose uptake by GLUT2
    2. Glycolysis (glucokinase for phosphorylation glucose), TCA cycle and oxidative phosphorylation > increasing ATP and ATP/ADP ratio
    3. Block ATP sensitive K+ (potassium, more inside cell) channel
    a. More positives stay inside > depolarisation > -30 mV from -80 mV.
    b. Na+ influx coupled to glucose uptake.
    4. Membrane depolarization
    5. Open Ca2+ channel (reaction on the depolarisation) > influx
    a. A second messenger > induces transport of the insulin vesicles to the plasma membrane and excretion (fusion with membrane).
    b. Cleavage to monomer form on insulin which is active.
    6. Insulin release
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10
Q

The liver cannot sense increased glucose levels in blood, while pancreatic beta cells do. How is glycogen storage induced in hepatocytes?

A

Insulin receptors

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11
Q

When stress, secretion of …

A

adrenaline by the adrenal gland

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12
Q

Most primary messenger cannot pass the PM, so binding

A

To cell surface receptor

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13
Q

Types of plasma-membrane receptors

A

-G-protein coupled receptor (GPCR) / 7TM receptor
> glucagon and epinephrine receptor
-Protein tyrosine kinase (PTK)
> insulin receptor

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14
Q

Name GPCRs and their general pathway

A

-Receptor activation by binding ligand (conformational change)
-Activation of the bound G-protein (GDP exchanged for GTP)
-Protein protein interactions for activation of transducing proteins and targets
> glucagon receptor, beta adrenergic receptors, chemokine receptors, taste and smell etc

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15
Q

K+-Na+-ATPase (pump)

A

Costs 1 ATP
2 sodium influx for 3 potassium efflux
> retain negative charge inside cytosol for voltage of -90mV over PM

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16
Q

Name a drug which can block the potassium channel to generate Ca2+ influx by depolarization and induce insulin release

A

Sulfonylurea

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17
Q

Pathway glucagon receptor and beta-adrenergic receptor

A

-Binding ligand
-Activation receptor
-Exchange GDP for GTP in G-alpha subunit of trimeric G protein
-Ga dissociates from G-delta,gamma and both are active (new G protein can bind active receptor: amplification)
-Gas activates adenylate cyclase by binding
-Adenylate cyclase catalyzes ATP to cAMP
-Second messenger cAMP activates proteins like Protein Kinase A (PKA) by binding and releasing regulatory subunits.

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18
Q

Structure PKA

A

Tetrameric when inactive (C2R2, catalytic/regulatory)
> cAMP binds the R-subunits and conformational change releases them and activates PKA

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19
Q

Amplification in glucagon and adrenaline pathways

A

-Activated receptor can bind and activate multiple trimeric G-proteins
-Activated G-protein can bind and activate multiple targets like adenylate cyclases
-Adenylate cyclase converts multiple ATP to cAMP.

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20
Q

Which receptor and pathway for the hormones angiotensin II and noradrenaline

A

Alpha-adrenergic receptor
> GPCR activated and G-protein activated (exchange) through Gaq
- Gaq activates Phospholipase C (PLC)
-PLC cleaves PIP2 to IP3 (free) and DAG (membrane bound)
-IP3 binds and opens IP3-sensitive Ca2+ channels on the ER membrane
-Ca2+ influx
-Ca2+ facilitates binding of DAG as activator to Protein kinase C (PKC)
-Activation PKC by releasing regulatory subunits

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21
Q

Ca2+, IP3 and DAG are…

A

second messengers

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22
Q

Cytosolic Ca2+ as second messenger

A

-Interaction with negatively charged oxygen atoms in bining proteins
-Able to cross link protein domains > conformational change (calmodulin, CaM)
- Subsequent binding and activation of other enzymes: CaM kinase bound and activation.

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23
Q

Rise in cytosolic Ca2+ essential for:

A

Glycogen metabolism (liver and muscle) and exocytosis (secretory cells)

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24
Q

Receptor tyrosine kinase function

A

-Binding ligand
-Dimerization intracellular domains upon binding
-Conformational change: kinase domains come nearby > trans-autophosphorylation of tyrosine residues by the tyrosine kinases
-Tyrosine kinases become fully active by this phosphorylation
-phosphorylate substrates, recruitment adaptors
> activatin of the target (PKB)

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25
Which amino acids can be phosphorylated?
Serine, Threonine, Tyrosine
26
Insulin pathway
1. Insulin induces conformational change in structure 2. Trans-auto-phosphorylation of tyrosines > docking sites for insulin receptor substrates (IRS) 3. Docking of PI3-K (kinase) to IRS-1 4. PIP2 > PIP3 5. Translocation of PDK1 to PM (PIP3-dependent protein kinase, serine/threonine kinase) 6. Phosphorylation and activation of PKB (Akt) 7. Akt targets are (in)activated by PKB/Akt
27
Muscle and adipose response to insulin
GLUT4 surface expression, insulin-dependent glucose transport > GLUT4 vesicles with GLUT4 in the cell, exocytosis when activated by insulin. > fasted state, no insulin, endocytosis > PKB and PKC promote translocation of GLUT4 vesicles to PM
28
Slow vs fast response to extracellular signal
Fast: altered protein function, slow: altered gene expression
29
Termination of signals in GPCRs
-Dissociation ligand-receptor -Internalization receptor-ligand complex by endocytosis -Phosphorylation receptor-ligand complex by GRK2 > binding beta-arrestin to block signal (remember, phosphorylations cost ATP) -GTPase activity by G protein: hydrolysis GTP to GDP, inactive G-protein and inactivation adenylate cyclase -cAMP degraded by cAMP-phosphodiesterase (cAMP-PDE) to AMP
30
Name a well known PDE inhibitor
Sildenafil (viagra), inhibits PDE 5 which converts cGMP to GMP
31
Epidermal growth factor (EGF) signaling
-EGF receptor binds EGF -Dimerization and trans-autophosphorylation -Binding adaptor Grb2 which binds adaptor Sos -Sos binds Ras in GDP form and induces exchange for GTP. > Ras signals for cell division and growth > Ras is a small GTP binding protein
32
Response in signalling after activation of the
effector(s)
33
HC08: How long do glucose stores last?
One day
34
Glycogen levels during day
Fluctuate: peaks after dinner and after breakfast
35
Healthy blood glucose
5 mM
36
Glucose homeostasis in times after fasting
-Short term: exogenous glucose -Up to 12 hrs: glycogenolysis -long term: gluconeogenesis
37
Why is blood glucose maintenance so important
Vital functions like the brain and erythrocytes depend on it
38
In which organs gluconeogenesis?
Liver and kidney
39
Gluconeogenesis is largely the reversal of glycolysis, except which steps?
The regulation steps
40
Regulation steps of gluconeogenesis
-Pyruvate carboxylase -Phosphofructokinase-2 complex -Glucose-6-phasphatase
41
In which tissues is glucose-6-phosphatase expressed?
Liver and kidney
42
The direction for enzymes that catalyze reaction both ways depends on ..
the concentration of the substrates
43
What energy is needed for gluconeogenesis
NADH and ATP (6 ATP)
44
Why are some steps irreversible
Huge change in Gibbs free energy
45
For which conversion from the reverse route of glycolysis in gluconeogenesis is a sideroute needed
Pyruvate to phosphoenolpyruvate (PEP) (animal PK cannot phosphorylate pyruvate) > detour through mitochondrion
46
Conversion pyruvate to PEP in gluconeogenesis
Pyruvate > Oxaloacetate > PEP From pyruvate (C3) to oxaloacetate (C4) > pyruvate carboxylase
47
Substrates pyruvate carboxylase
Pyruvate, CO2 in the form of HCO3- (bicarbonate, hydrogen carbonate), ATP
48
Where is pyruvate carboxylate located
Mitochondrial matrix
49
How is oxaloacetate transported from mitochondial matrix to cytosol
Malate shuttle > oxaloacetate to malate using 1 NADH, transport to cytosol, make oxaloacetate and yield the NADH back
50
Conversion oxaloacetate to PEP/phosphoenolpyruvate in cytosol
Oxaloacetate + GTP > PEP + GDP + CO2 (by PEP carboxykinase in cytosol)
51
Regulation pyruvate carboxylase
-Activation by acetyl-CoA -Inhibition by ADP
52
Regulation PEP carboxykinase
Inhibition by ADP
53
Reciprocal regulation of glycolysis and gluconeogenesis
By Fructose-2,6-bisphosphate > activation PFK-1 > inhibition F-1,6-BPase (gluconeogenesis: F-1,6-P > F-6-P)
54
Regulation Fructose-1,6-bisphosphatase
Inhibition by F-2,6-BP and AMP Activation by citrate
55
How is PFK-2 inactivated and FBPase2 activated simultaneously?
PKA phosphorylates the PFK-2 domain of the bifunctional enzyme which activates FBPase2 > Insulin promotes phosphoprotein phosphatase and therefore PFK-2 by dephosphorylating it. > F-6-P promotes the phosphatase as well > Glucagon (or adrenaline) stimulates PKA and therefore FBPase2 > PFK-2 promotes formation F-2,6-BP which promotes glycolysis while inhibiting gluconeogenesis. > FBPase2 prevents formation of F-2,6-BP (phosphatase)
56
Function Glucose-6-phosphatase
Convert G6P to glucose to export it to blood, increase blood glucose levels > only in liver and kidney
57
Where G6Pase activity?
ER luminal side of ER membrane > T1 imports G6P > G6Pase converts to glucose and Pi > Pi export out of ER using T2 > glucose exports with T3
58
Substrate and precursors for gluconeogenesis
Substrate: pyruvate (2) Precursors: lactate, some amino acids, glycerol > lactate (oxidation, yield NADH) and alanine and other C3 amino acids converted to pyruvate > C4 and C5 amino acids anaplerosis and through conversion to oxaloacetate entering > Glycerol converted (C3) to Glycerol-3-P which can be oxidized (yield NADH) to triose-P
59
Cori cycle
Lactate from anaerobic glycolysis transported to liver via blood and gluconeogenesis and glucose back to muscle for anaerobic glycolysis
60
Glycerol can be used for gluconeogensis. Can FAs be as well?
No (often not)
61
Prosthetic group of pyruvate carboxylase
Biotin (vitamin B7) > biotin is the carrier of activated CO2 (HCO3-)
62
Which molecule is essential for pyruvate carboxylase to work
Acetyl-CoA > allosteric activator
63
Fatty acids are required for gluconeogenesis but cannot be converted. explain
Generate energy (ATP, GTP) for gluconeogenesis and to activate pyruvate carboxylase through acetyl-CoA
64
Acetyl-CoA (breakdown product FA oxidation) cannot be used to make glucose, explain
Acetyl-CoA (C2) cannot be converted to pyruvate (PDH step is irreversible) > goes into TCA cycle, broken down into CO2
65
Futile cycle glycolysis and gluconeogenesis costs
Waste of energy: is avoided through reciprocal regulation > 2 ATP + 2 GTP + 4 H2O > 2 ADP + 2 GDP + 4 Pi > gluconeogenesis costs 2 NADH as well, but same yield in glycolysi
66
Gluconeogenesis from 2 pyruvate to 1 glucose costs
6 NTPs > 4 ATP and 2 GTP
67
distribution gluconeogenesis
90% in liver and 10% in kidney
68
HC09: energy release from ATP hydrolyses reactions
-ATP + H2O > ADP + Pi: dG: -30.5 kJ/mole -ADP + H2O > AMP + Pi. dG: -30.5 kJ/mole -ATP + H2O > AMP + PPi: dG: -40.6 kJ/mole -PPi + H2O > 2 Pi: dG -31.8 kJ/mole -AMP + H2O > A + Pi (-12.6 kJ/mole)
69
ATP has how many energy rich ... bonds
2 phosphoanhydride bonds > unstable, negative charges
70
Energy rich bond in acetyl-CoA
Thioester bond
71
Metabolic roads to acetyl-CoA predominantly in the ...
mitochondria
72
The mitochondrial inner membrane folds into ...
Cristae
73
Dynamism of mitochondria
Fusion and fission, also mitophagy (then recycling) by autophagy or apoptosis induction by release cytochrome c
74
Which chain of enzymes is found in inner mitochondrial membrane?
Electron transport chain (respiratory chain)
75
Proton motive force
delta p = chemical gradient (delta pH based on concentrations) + charge gradient (d w) > electrochemical gradient
76
Highly regulated transport over mitochondrial membranes?
Outer membrane: no special transport needed, porous, free entry Inner membrane: selective, transporters needed.
77
ATP is produced in a process called ...
intermediate metabolism > glucose is oxidized in controlled way, to release its energy in the form of ATP > glycolysis, PDH oxidative decarboxylation, mitochondrion, oxidative phosphorylation
78
Where PDH oxidative decarboxylation?
In mitochondrial matrix
79
TCA cycle generates ...
3 NADH + H+ 1 FADH2 1 GTP
80
NADH carries ... high energy electrons
2 (hydride ion) dE0= 61.2 kJ/mole
81
Electron transport chain + ATP synthase numbered
Complex I: NADH dehydrogenase Complex II: succinate dehydrogenase (no protons pumped for proton gradient) Complex III: cytochrome b-c1 Complex IV: cytochrome oxidase Complex V: ATP synthase
82
Complex II is an ... of the TCA cycle
Enzyme > succinate dehydrogenase converts succinate into fumarate, reducing its prosthetic (tightly bound) group FADH2. > contains Fe-S cluster (iron sulfur) to transport electrons. > donates electrons to Coenzyme Q to deliver it to complex III > skips complex I: less ATP yield because less protons pumped through FADH2
83
Complex I gives energy rich electrons after pumping ... protons to the intermembrane space to ..
4 protons pumped, electrons give to Coenzyme Q
84
How many protons do complex III and IV pump
2 (III) and 4 (IV) respectively
85
What is the electron acceptor at complex III?
Cytochrome c
86
Is FADH2 generated in tca a regulator of many enzymes except complex II?
No, FADH2 is stuck in the enzyme (it is a protein, prosthetic group)
87
What happens to leftover low energy electron at complex IV
Molecular oxygen will happily receive them as acceptor > reduction to water.
88
What happens to the generated proton gradient
Proton motive force used to generate ATP through transport through ATP synthase back to matrix > proton gradient has a maximim like a battery: electron transport chain is stopped because the extra protons cannot be used anymore: and TCA cycle stops because too much NADH and no NAD+
89
Coenzyme Q and cytochrome c are ... of the electron transport chain
Electron shuttles
90
Which of the electron transport chain molecules contain iron sulfur clusters?
Complex I, II, III
91
What is CoQ as molecule
A lipid > 10 isoprene units and quinone head group
92
Reduction CoQ
CoQ ubiquinone Q (oxidized form) > one electron transfer + H+ - Semiquinone, free radical, Q*- > one electron transfer + H+ -Ubiquinol CoQH2 (QH2, reduced form)
93
NADH has allosteric influence, why not FADH2 as regulator of other enzymes
It is tightly bound by enzymes as prosthetic group so cannot move freely (flavoprotein)
94
Which enzyme in cellular respiration besides succinate dehydrogenase has FAD as prosthetic group?
E3 of the PDH complex
95
HC10: FADH2 has ... energy conserved than NADH
less
96
FADH2 is a flavoprotein, is it soluble?
No
97
How many NADH + H+ needed to reduce one molecular oxygen O2?
2 NADH + 2 H+ > four protons needed and Electrons needed
98
Reaction in cytochrome c oxidase (Complex IV)
Four substrate protons and four translocated protons: 4 cyt c-red + 8 H+ (matrix) + O2 > 4 cyt c-ox + 2 H2O + 4 H+ (intermembrane space)
99
Reducing oxygen at complex IV is an .. reaction (endo/exo)
Exergenic reaction
100
The catalytic mechsnism of cytochrome c oxidase represents a
cycle > the electron transfers is coupled to proton translocation across the inner mitochondrial membrane.
101
What happens at high ATP?
ATP synthase stops > proton gradient builds up to maximum and oxidative phosphorylation comes to complete stop > No respiratory control, no TCA cycle (coupled systems), too much NADH and no NAD+ to keep TCA cycle running
102
ATP synthase structure
-c subunits of the F0 (integrated in inner membrane) > each bind one proton and rotate -Alpha and beta subunits of the F1 headpiece (hangs into matrix) remain static -Central gamma subunit of F1 rotates, changing the conformation of the beta subunits
103
Conformations of beta subunits ATP synthase
-From loose: binding ADP and Pi -Via tense (after rotation): squash ADP and Pi together to make ATP -To open: releasing ATP > three beta subunits in headpiece which changes constantly in this order (loose, tense, open) > ATP release with each conformational change
104
Price of ATP generation when respiratory chain completely reduced
Respiratory chain completely reduced and oxygen present > ROS -electron stolen from the process by oxygen -Three ROS >Superoxide (O2*-), hydrogen peroxide (H2O2), Hydroxyl radical (*OH) (+ hydroxide OH-, no ROS) > through one electron reduction reactions from O2 to 2 H2O as intermediates
105
ROS come mostly from complexes ...
I and III NADH dehydrogenase and cytochome b-c1 complex
106
When superoxide production by complex I
Reperfusion injury > reverse electron transport > equilibrium reactions: reverse possible > chance of making superoxygen reactants.
107
Supercomplex increase ... and reduce ...
increase efficiently and reduce ROS formation > cristae reconfiguration> bring complexes together to respiratory supercomplex
108
Which enzyme nutralizes superoxide (O2*-)
Superoxide dismutase (SOD) > O2*- + O2*- + 2H+ > H2O2 (hydrogen peroxide) - electron transfer attracts protons to neutralize -GPX converts H2O2 to H2O
109
Can the hydroxyl radical be neutralized
No, you are screwed.
110
ROS signaling
ROS because of exercise or hypoxia etc activates TFs, and leads to gene transcription of antioxidant enzymes, phase I and II detoxifying enzymes, UCP1 > increases health and lifespan
111
Mitohormesis
reduced amount of mitochondrial stress is beneficial for health because of ROS signaling, but too much is dangerous and deadly
112
Uncoupling
If energy is not caught as ATP, it is lost as heat
113
Chemical uncoupling agent
Dinitophenol (DNP), used to 'burn fat' > high H+ concentrations causes outside protons to bind to DNP molecules > transfer DNP across inner mitohondrial membrane > low H+ in matrix causes dissociation of DNP molecules > generation heat > energy and thus fat when fasting used for energy, but no ATP generation thus the respiratory chain and TCA cycle and burning of fat continues > patients may die to hyperthermia and too low ATP when overdose
114
Uncoupling in brown fat
Uncoupling protein (UCP-1, thermogenin) in babies and adults > proton motive force used for movement into matrix without coupling to ATP synthase but rather through UCP-1 transporter which releases the energy as heat > protons shake while brought back to matrix which gives heat

Medical Biochemistry and Pathophysiology (16 decks)

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