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Medical Biochemistry and Pathophysiology > Week 1B: Metabolism Basics, Organs and metabolic pathways, glycolysis and pentose phosphate pathway, TCA cycle > Flashcards

Week 1B: Metabolism Basics, Organs and metabolic pathways, glycolysis and pentose phosphate pathway, TCA cycle Flashcards

HC03-06

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USMLE® Step 1 flashcards
1
Q

HC03: Energy methods out of glycolysis

A

-NADH
-ATP

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2
Q

Requirement of free energy for:

A

-Mechanical work: cellular transport, muscle contraction
-Active transport of molecules and ions
-Synthesis of macromolecules from building blocks
-Thermogenesis

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3
Q

Energy is obtained from the … of food

A

oxidation

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4
Q

Metabolism consists of … pathways of chemical reactions

A

Interconnected

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5
Q

Anabolism

A

Synthesis of complex molecules
- useful energy + simple precursors > complex molecules
- Gluconeogenesis of glucose from pyruvate or lactate for example

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6
Q

Catabolism

A

Breakdown
> Carbohydrates and fats to CO2, H2O and useful energy
> Glycolysis of glucose

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7
Q

Metabolism is regulated, why?

A

You don’t want to make something and break it down simultaneously
-Glycolysis yields 2 ATP
-Gluconeogenesis costs 6 ATP
> organize the fluxes

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8
Q

The currency of free energy

A

ATP: adenosine triphosphate

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9
Q

ATP structure

A

Adenine, ribose and 3 phosphates

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10
Q

How many energy rich bonds does ATP have and how are they called?

A

Two phosphoanhydride bonds
> Gamma and beta phosphates are energy rich bond
> the outer bond (gamma) is between two phosphates (both negatively charged)
> alpha bond not between two phosphates, lower energy

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11
Q

ATP can be converted to … to release energy

A

ADP, or AMP

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12
Q

dG and entropy formula

A

dG = dH - T*dS
dG: delta Gibbs free energy
dH: delta enthalpy (heat content)
dS: entropy: degree of disorder

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13
Q

ATP>ADP+Pi is an … reaction (hydrolysis)

A

Exergonic (energy released for Gibbs free energy)

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14
Q

What is the dG0’ of ATP > ADP

A

-30.5 kJ/mole

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15
Q

What if dG0’ is negative?

A

Spontaneous reaction
> can be coupled to an energetically unfavorable reaction

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16
Q

Why are phosphoanhydride bonds energy rich

A

-A lot of resonance structures available where the energy can be located
- Force of the negative charges who lay in close proximity
> ATP 4- > outer phosphate 2- and middle and inner 1-

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17
Q

dG0’ of ATP > AMP + PPi. When is this used?

A

dG0’=-45.6 kJ/mole
> used if the energetically unfavorable reaction has a dG0’ > 30.5 kJ/mole

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18
Q

In which organisms is the ATP-ADP cycle the fundamental mode of energy exchange?

A

All

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19
Q

Why are phosphoenolpyruvate, 1,3-BPG and creatine phosphate, with a more negative dG0’ for conversion less good as energy currency

A

These compounds can be used to phosphorylate ATP fro ADP
> you can synthesize ATP without oxidative phosphorylation in mitochondria if higher energy molecules are oxidized. If the currency is a maximal energy carrier, this is not easily possible.

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20
Q

How is it called if high energy compounds are used/oxidized to make ATP? How much of the ATP is made through this mechanism?

A

Substrate-level phosphorylation (10%)

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21
Q

Creatine usage before exercise

A

In muscle cells, you make creatine phosphate using ATP before the sport in rest
> During exercise, creatine phosphate can be used to synthesize ATP as early reserve for substrate-level phosphorylation
> for sudden exercise
> oxygen cannot hold up with muscle activity, the oxidative phosphorylation cannot keep up with the use of ATP, creatine supplementation to make ATP with substrate level phosphorylation on short term

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22
Q

Creatine is synthesized in our …

A

Liver and kidneys

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23
Q

Creatine phosphate + ADP <=> ATP + creatine: enzyme?

A

Creatine kinase

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24
Q

ADP+ADP <=> ATP + AMP. Explain and enzyme

A

It costs two ATP to regenerate ATP from AMP. Enzyme is adenylate kinase
> this reaction is used when ATP levels run low in human cells including muscle. Produce ATP from ADP for extra energy
> AMP is useless until regeneration by AMP kinase if there is much AMP

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25
Q

Sources of ATP during exercise

A

Seconds: ATP reserve and creatine phosphate
Minutes and hours: Anaerobic and aerobic metabolism (ATP regeneration)

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26
Q

In initial seconds after cold start, ATP is regenerated by …. from ADP and creatine phosphate, followed by metabolic pathways

A

High-phosphoryl transfer

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27
Q

Oxygen uptake during exercise

A

At start, oxygen uptake increases exponentially, until a steady state is reached
> first minutes exercise: shortage of oxygen
> substrate level phosphorylation is then essential for energy supply

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28
Q

Human muscle fibers

A

-Type I: slow twitch: long time (hours), aerobically, low power, high density mitochondria, 80msec till peak contraction
-Type IIa: fast twitch a/ intermediate: <30min, middle power, middle density mitochondria, 30 sec till peak
-Type IIb: fast twitch b: High intensity, <5 minutes exercise, low density mitochondria, anaerobically.
> most fibers I, than IIa, than IIb

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29
Q

Human body contains approx … g of ATP, and at rest we need …

A

100
at rest: 40 ATP a day
> high turnover is required for the relatively small amounts of ATP

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30
Q

ATP used for..

A

-Motion, without it muscles freeze. To return actin-myosin to relaxed state (crossbridge cycle)
-Active transport: in muscle, Ca2+ ATPase uses ATP for transport Ca2+, needed in contraction
-Biosynthesis
-Signal amplification

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31
Q

Most efficient fuel

A

Fats

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32
Q

Redox reaction principles

A

Reduction: gain of electrons
Oxidation: loss of electrons
Electron transfer from reduced compound (oxidation) to the oxidized compound (reduction)

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33
Q

Oxidation states of C1’s go in …

A

two electron reactions
Most energy (reduced)
Methane CH4 (-4)
- 2 e-
Methanol (hydroxyl) CH3OH (-2)
Formaldehyde (aldehyde, ketone) HC(=O)H (0)
Formic acid (carboxyl) HC(=O)OH (+2)
Carbon dioxide (O=)C(=O) (+4)

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34
Q

Most important fuels

A

Glucose and fats
> fats more efficient, because the carbon atoms are in a more reduced state

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35
Q

Direct burning of sugars

A

All Gibbs free energy released as heat, waste

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36
Q

Glucose oxidation in the cell

A

In small steps by enzymes to tranfer Gibbs free energy to carrier molecules

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37
Q

How many steps for glucose to pyruvate

A

10

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38
Q

Why does something change upon phosphorylation of a protein

A

Different charges negative on phosphorylated site

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39
Q

Conformational change after phosphorylation Ca2+ ATPase

A

Calcium ion flips out (transport over membrane) on the other site because of conformational change of teh ATPase which spans over the membrane > into lumen
> dephosphorylation and reset for next cycle

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40
Q

Oxygen wants to …

A

take up electrons (acceptor)
> carbon and oxygen next to it: unfortunate, electron gets pulled awat
> carbons have more electrons with just hydrogens next to it

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41
Q

Energy in glycolysis is released in oxidation of an aldehyde (GAP, glyceraldehyde 3-phosphate) to a carboxylic acid (3-phosphoglyceric acid). How?

A

Through intermediate step, energy of oxidation is first trapped as high potential phosphate group
> two electrons plus H+ ion (hydride ion H-) released and captures by electron carrier NAD+
> GAP + NAD+ + HPO4- > 1,3-BPG (intermediate) + NADH + H+
> 1,3-BPG (1,3-bisphosphoglycerate) + ADP > 3-phosphoglyceric acid (with extra OH at place of phosphorylation for intermediate, carboxyl end) + ATP

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42
Q

Oxidation GAP to yield ATP is an example of

A

Substrate-level oxidation

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43
Q

When is Gibbs free energy stored in ion gradients over membranes?

A

Proton gradient, fueled by oxidation of fuels by special proton pumps
> oxidative phosphorylation in mitochondria
> yields 90% of the ATP

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44
Q

Energy extraction from food

A

1: macromolecules are broken down into small units (stage 1)
2: breakdown to acetyl group of acetyl-CoA, a central metabolite
3: ATP production through the oxidation of the acetyl group of acetyl-CoA

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45
Q

Activated carriers in metabolism

A

-ATP: phosphate groups high potential
-NADH and FADH2: activated carriers of electrons during oxidation of fuels
-NADPH: activated carrier of electrons for reductive biosynthesis
-Coenzyme A: activated carrier of carbons

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46
Q

Characteristics NADH and NADPH

A

-Water soluble co-enzymes that carry electrons
-Contain nicotinamide ringwith reactive site at the carbon opposite to the N.
> different R groups in standard structure, in NAD+: H, in NADP+: PO3(2-)
-NADH for oxidative phosphorylation and NADPH for reductive biosynthesis

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47
Q

What do NAD+ and NADP+ accept to be reduced?

A

A hydride ion: H+ with two e-.
> in addition, a second H+ is split of the molecule which is oxidized by NAD+ and appears in the solvent

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48
Q

Reactive sites FAD+

A

Two nigle N’s on the FMN (flavine mononucleotide)

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49
Q

Characteristics FAD

A

In flavoproteins, a FMN or FAD (flavine adenine dinucleotide) are tightly bound co-enzymes: prosthetic group.
> FAD is more flexible than NAD+ and can participate in transfer of single hydrogen atom (electron and proton) or in the transfer of two H atoms.

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50
Q

Reducing FAD

A

The two hydrogen atoms are transferred to FAD to form FADH2. The two H are added to the free N in the three ring structure

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51
Q

Which electron carrrier can participate in the most diverse set of reactions?

A

Flavoproteins instead of NAD(P)-dependent enzymes > can catalyze transfer of one or two electrons

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52
Q

Redox enzymes

A

Oxido-reductases

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53
Q

Which enzymes remove hydrogen atoms?

A

Dehydrogenases

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54
Q

Function oxidase?

A

Transfer of only electrons. Uses molecular oxygen O2 as the acceptor of the electrons from the oxidized compound.

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55
Q

Function oxigenase

A

Oxidizes a compound by adding O2 from molecular oxygen to it

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56
Q

Complex IV function (cytochrome c oxidase)

A

Transfers electrons to molecular oxygen which is reduced to water
4 Cytochrome c red + 4H+ + O2 > 4 Cytochrome c ox + 2 H2O

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57
Q

Number of valency electrons in O2 an H2O

A

Octa valency rule but for hydrogen just two (2 stripes, 4 electrons)
O2: 2 * 6 = 12
H2O: 8 (2 stripes = 4 from O, 1 stripe = 2 per H)

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58
Q

Successive one-electron reductions of molecular oxygens

A

Oxygen (O2)
> Superoxide anion (O2-)
> Hydrogen peroxide (H2O2) (addition 2 H+)
> Hydroxyl radical (OH) + hydroxide (OH-)
> 2 H2O water (addition 2 H+)

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59
Q

The three reactive oxygen species (ROS)

A

Three intermediates in oxygen reduction to water
> Superoxide (O2-)
> Hydrogen peroxide (H2O2)
> Hydroxyl radical (OH)

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60
Q

Most dangerous ROS

A

Hydroxyl radical (*OH), the most reactive free radical, initiates oxidative destruction of biomolecules

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61
Q

What group is transferred by a dehydrogenase?

A

A hydride ion (two electrons and H+) > oxidation.

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62
Q

Lactate dehydrogenase reaction

A

Lactate > pyruvate
Using NAD+ to accepts the hydride ion

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63
Q

Effect of high levels of NADH on gluconeogenesis

A

High levels of NADH inhibit the oxidation of lactate to pyruvate in the liver
> reduction liver pyruvate to lactate
> Hypoglycemia and lactate acidosis

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64
Q

Cori cycle

A

In muscle:
Glucose > pyruvate > lactate (yields 2 ATP)
to blood to liver
Lactate > pyruvate > glucose (costs 6 ATP)
glucose to blood to muscle

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65
Q

The TCA ccle has two simple oxidation reaction catalyzed by

A

-Succinate dehydroenase (succinate > fumarate)
-Malate dehydrogenase (malate > oxaloacetate)
> yield NADH

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66
Q

Oxidative decarboxylation reactions in TCA cycle with oxidation which also yield NADH (also oxidation)

A

-Isocitrate dehydrogenase (isocitrate + NAD+ > a-ketoglutarate + CO2 + NADH + H+)
-a-ketoglutarate dehydrogenase (a-ketoglutarate + NAD+ + CoA > succinyl-CoA + CO2 + NADH + H+)

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67
Q

How many electrons for reduction oxygen to water?

A

4 electrons

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68
Q

Difference oxygen and carbon reaction

A

Oxygen deals with one electron and carbon only with two (often hydride ion)

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69
Q

Which compounds are needed to bind ROS in oxidation O2?

A

Transition metals

70
Q

CoA reactive group and carry of acetyl-CoA

A

The HS- which can form a high energy thioester bond with an carboxyl group.
> acetyl-CoA carries an activated acetyl group.

71
Q

dG0’ of acetyl-CoA + H2O > acetate + CoA

A

-31.4 kJ/mole
> high potential thioester bond: -C(=O)-S-CoA
> costs ATP > AMP + PPi (so 2 ATP) to form because 45.6>31.4>30.5 kJ/mole

72
Q

When is the released energy of thioester bond in CoA carrier used

A

For example in reductive biosynthesis of cholesterol
> HMG-CoA + 2 NADPH + 2 H+ > mevaonate + 2 NADP+ + CoA (HMG-CoA reductase, committed step)

73
Q

H05: Carbohydrate metabolism catabolism

A

Glucose > energy and CO2 and H2O
-Glycolysis
-Pyruvate oxidation (or reduction to lactate, anearobic glycolysis)
-Citric acid cycle
-Electric transport / respiratory chain
-ATP synthesis

74
Q

Respiratory chain + ATP synthesis =

A

oxidative phosphorylation

75
Q

HC04: Metabolism is regulated through control of (3):

A

-Amount of enzymes
-Catalytic activities of enzymes (hormonal control, allosteric control)
-Accessibility of substrates (compartmentilization)

76
Q

Energy intake vs expenditure

A

-Intake through diet: fat, protein, carbohydrate, alcohol
-Expend through thermogenesis, physical activity and basal metabolic rate

77
Q

Food is broken down to acetyl-CoA. Fates acetyl-CoA and pyruvate

A

Glucose <=> pyruvate
Pyruvate > (irreversible reaction) acetyl-CoA
Acetyl-CoA
> CO2 (irreversible, oxidation to CO2, TCA cycle for energy)
<=> lipids (storage as fats)

78
Q

Reaction to insulin in glucose uptake

A

Increased uptake glucose by muscle cells and adipocytes

79
Q

Which organ is primarily responsible for maintaining blood glucose levels?

A

The liver

80
Q

States of energy

A

Fed state: insulin rules, anabolic
Fasted state: glucagon rules, catabolic
> pathways directed in liver by hormones

81
Q

Endocrine pancreas cells

A

-Alpha cells: synthesize insulin
-Beta cells: synthesize glucagon
-Insulin inhibits the alpha cells from making glucagon
> in islets of Langerhans

82
Q

Exocrine pancreas makes

A

Digestive enzymes

83
Q

Diabetes mellitus type 1 cause

A

Autoimmune response against own pancreatic beta cell > low insulin, high glucagon (no inhibition, even when hyperglycemia)

84
Q

If the blood glucose is high than

A

The beta cells secrete insulin

85
Q

Insulin effects

A

It stimulates anabolic anabolism of glycogen and fatty acids, but inhibits gluconeogenesis (because gluconeogenesis in fasted state)

86
Q

When fuel for energy

A

Always but not in the fed state when there is enough ATP, storage to fatty acids or glycogen

87
Q

Main consumers glucose

A

Brain and erythrocytes

88
Q

When hypoglycemia

A

Blood glucose «4.5 mM

89
Q

Glucose metabolism in fed state

A

Glucose from gut to portal vein and insulin secretion by pancreas to liver, adipocytes, muscle and all tissues as well.
> Liver converts a part of the glucose to glycogen
> Tissues take up glucose for fuel or for biosynthesis: brain, adipocytes, erythrocytes, muscle cells
> Muscle cells make glycogen

90
Q

Glucose can exit the liver after activation to glucose-6-phosphate because it expresses the enzyme

A

G6Pase: Glucose-6-phosphatase

91
Q

Glucose metabolism in fasted state

A

Alpha cells in pancreas secrete glucagon
> Glycogen breakdown in liver and transport to the brain and erythrocytes via blood.
> Blood has no mitochondria: anaerobic glycolysis and transfer lactate to liver for conversion to glucose

92
Q

Fat metabolism in fed state

A

Glucose and amino acids from gut to portal vein to liver
> Fat from gut through enterocytes and as chylomicrons through lymphatics to blood and TAGs are taken up by muscle cells and adipocytes as FAs (LPL activity)
> secretion insulin
> Liver: glucose to glycogen, and glucose and aminoacids acetyl-CoA to use acetyl-CoA to make fatty acids
> Fatty acids in liver used to make TAGs: transport through VLDL to blood for periphery.
>Muscle uses fatty acids for energy or storage as TAG
> adipocytes store FAs in TAGs

93
Q

Fat metabolism in fasted state

A

Glucagon rules
> Liver: glucose to blood to brain and erythrocytes
> breakdown TAGs in adipocytes to FAs, and transport to liver via blood. Liver converts it to acetyl-CoA and uses it for energy
> Muscles take up FAs from blood and convert it to acetyl-CoA for oxidation for energy

94
Q

Amino acid metabolism in fasted state

A

glucagon rules
> breakdown proteins to amino acids in gut > to liver via portal vein
> conversion amino acids to glucose in liver for brain and erythrocytes

95
Q

Precursors gluconeogenesis (in liver) in fasted state to provide glucose to brain and erythrocytes mainly

A

Amino acids from dietary proteins, lactate from erythrocytes, glycerol from lipolysis in adipocytes.

96
Q

Central metabolite which interconnects the glucose, fat and amino acid metabolism

A

Acetyl-CoA

97
Q

Metabolism in untreated T1DM

A

No insulin, glucagon rules
- GLUT4 not upregulated: no uptake glucose by adipocytes and muscle cells, just erythrocytes and brain. And glycogen breakdown even when uptake glucose and amino acid conversion to glucose > glucose accumulation
- Protein breakdown in muscle and alanine transport to liver and making glucose there
-Glucagon promotes lipolysis in adipocytes: FAs accumulate in blood (FFAs to serum albumin)
-FAs in liver converted to VLDL with TAGs (accumulate in blood) and ketone bodies (accumulate in blood)

98
Q

Increasing activation of muscle fibers with increasing force

A

Type I > Type IIa > Type IIb
- Type I fiber takes the largest burden during light exercise, this decreases during intenser exercise (also more used, but relatively less because also other fibers used now)

99
Q

Energy sources during exercise

A

-Increasing efforts: use of blood glucose and muscle glycogen increases while use of muscle fat and blood free fatty acids decrease.
> maximum effor: glycogen is the preferred energy source

100
Q

HC05: Glycolysis entails the oxidation of .. to

A

glucose to 2 pyruvate which yields NADH and ATP

101
Q

There is …. ATP transport across mitochondrial membrane

A

Coupled antiparallel transport

102
Q

Expression different GLUT transporters and glucokinase/hexokinase in tissues

A

Gut: GLUT2
Pancreas beta cells: GLUT2 and GK
Liver: GLUT2 and GK
Brain: GLUT3 and HK
Erythrocytes: GLUT1 and HK
Muscle and adipocytes: GLUT4 and HK

103
Q

Km and character of GLUT2

A

GLUT2 for high concentrations glucose in lumen gut import for transport to liver
> expressed by gut, pancreas and liver
> high Km, low affinity (20 mM)
> a lot of the glucose will pass the liver via GLUT2 to the blood stream

104
Q

Where GLUT1/3 expression, and characteristics

A

In all mammalian tissues
> For basal glucose uprake
> low Km (1 mM), high affinity
> in brain much expression GLUT3: high affinity, much glucose needed, just like GLUT1 for erythrocytes (much glucose needed, only glycolysis)

105
Q

GLUT4

A

In muscle cells and adipose cells: high Km, low affinity (5 mM) and insulin-dependent
> glucose uptake in diabetics patients after insulin injection
> only when insulin rules, in fed state
> the Km is 5 mM, equal to the blood glucose 5 mM. For GLUT1/3 Km 1 mM < 5 mM

106
Q

Why glucose transporters?

A

Glucose is hydrophilic and cannot pass the membrane

107
Q

Sodium glucose linked transporter 1 (SGLT1)

A

Facilitates active transport of glucose over PM in the enterocytes of the gut > low sodium concentration in cytosol and high in lumen small intestine > cotransport glucose and sodium
- costs ATP hydrolysis to restore sodium balance (low inside cell) with a Na-K ATPase on the basal membrane
-Glucose to blood from intestinal cell with concentration gradient through glucose permease
- active transport makes sure that all glucose is taken up, so the uptake is not completely dependent on the high affinity GLUT2.

108
Q

Pyruvate fates for energy in exercizing muscle cells

A

-Last seconds of sprint: low O2, pyruvate reduction to lactate
-Normal: oxidation pyruvate in mitochondria after decarboxylation to acetyl-CoA

109
Q

First stage glycolysis

A

Investment: 2 ATP used
> activation glucose to keep it inside the cell
> Hexokinase enzyme phosphorylates glucose to glucose-6-phosphate (cannot pass PM)
-phosphorylation destabilizes the glucose (give energy for reaction)

110
Q

Product inhibition hexokinase

A

At high concentrations, G-6P inhibits hexokinase

111
Q

How does glucose bind hexokinase

A

To the subtrate binding site and induced fit

112
Q

Hexokinase isozymes

A

-Hexokinase 1: muscle and brain
> low Km: high affinity
> product inhibition by G-6P
-Hexokinase 4/ glucokinase
> high Km, low affinity
> not inhibited by G-6P
> In liver: glucose should not stay, only if there is excess glucose, it should be taken up and converted, because liver has to deal with it.

113
Q

Where expression Hexokinase 1 and where glucokinase?

A

Glucokinase in pancreas, GI tract and liver: only use and retain glucose in the fed state
Hexokinase 1 in brain, adipose tissue and muscle tissue and erythrocytes: need glucose for energy and function.

114
Q

Investment phase of glycolysis summed

A

Two phosphorylation steps
> Glucose to fructose-1,6-bisphosphate
-Glucose > G-6P (costs ATP, hexokinase)
-G-6P <=> Fructose 6-phosphate (phosphoglucose isomerase)
-F6-P > F-1,6-BP (costs ATP, phosphofructokinase)

115
Q

Stage 2 of glycolysis

A

Fructose-1,6-bisphosphate (C6) is split into two C3 molecules by aldolase
- to DHAP (dyhydroxyacetone phosphate) and GAP (glyeraldehyde 3-phosphate)

116
Q

Percentage products of conversion F-1,6-P by aldolase

A

96% DHAP
4% GAP > toxic, will attack proteins

117
Q

Conversion glyceraldehyde 3-phosphate to dihydroxyacetone phosphate by the enzyme…

A

TIM enzyme: triose phosphate isomerase.
> diffusion controlled
> both sides reversible
> but GAP is the one used in stage 3

118
Q

Stage 3 glycolysis

A

Oxidation steps to pyruvate
> yield 2 ATP and 1 NADH per C3 product
> 4 ATP produced in total
> net: 2 ATP production (2 invested)
> Take energy in electrons by transferring 1 hydride ion to NAD+ per C3 split product

119
Q

Sum reaction glycolysis

A

Glucose + 2 Pi + 2 ADP + 2 NAD+ > 2 pyruvate + 2 ATP + 2 NADH + 2 H+ + 2 H2O

120
Q

Fates pyruvate

A

-To acetyl-CoA, oxidation further in mitochondria
-To lacate to regenerate NAD+
-To ethanol via acetaldehyde (decarboxylation and reduction) to regenerate NAD+)

121
Q

Anaerobic glycolysis

A

Making lactate from pyruvate using lactate dehydrogenase

122
Q

Which steps in glycolysis are tightly regualted?

A

The irreversible ones

123
Q

Regulated steps glycolysis: the reactions and enzymes

A

-Glucose> Glucose-6-P (hexokinase)
-Fructose -6-P > Fructose 1,6-bisphosphate (PFK-1)
-Phosphoenolpyruvate (PEP) > pyruvate (Pyruvate Kinase/ PK)

124
Q

Thermodynamics at regulated steps glycolysis

A

Reactions with dG &laquo_space;0

125
Q

Regulation phosphofructokinase-1 in muscle

A

PFK-1
> promoted by high [AMP]
> inhibited by high [ATP], citrate, or low pH (anaerobic glycolysis)
-High ATP or citrate indicate high energy status of the cell

126
Q

ATP/AMP ratio in cell through

A

Adenylate kinase
ADP + ADP <=> AMP + ATP
- high AMP: low energy status cell
-High ATP: high energy status cell

127
Q

Regulation glycolysis in resting muscle

A

It is off!
High G-6-P inhibits HK
ATP and citrate inhibit PFK-1 and PK

128
Q

Regulation glycolysis in active muscle

A

Glycolysis is on
> ATP/AMP ratio low (high AMP) promotes PFK-1
> F-1,6-BP promotes PK (feedforward stimulation)

129
Q

Liver blood sugar homeostasis

A

If blood glucose is high, it still needs to take up glucose and hold it to make glycogen (no product inhibition by G-6-P)
> then inhibition gluconeogenesis and promotion glycogen storage

130
Q

Regulation glycolysis in liver

A

-GK: low affinity for glucose, high KM. No product inhibition
-PFK-1: ATP regulation like in the muscle, no effect of low pH, but citrate does inhibit PFK-1 (enhances effect ATP)

131
Q

Regulation PFK-1 in liver through PFK-2

A

PFK-2 can convert F-6P to F-2,6-BP.
-F-2,6-BP is a metabolite which regulates glycolysis/gluconeogensis balance in liver.
-F-2,6-BP produced by PFK2 and dephosphorylated by FBPase2
> 2 catalytic domains on one protein (PFK-2/FBPase2)
-F-2,6-BP activates PFK-1 (lower Km, slightly increases Vmax)

132
Q

Regulation PK in liver

A

-Phosphorylated form is less active
-Dephosphorylated form in more active
-Phosphorylation PK in low blood glucose level and dephosphorylation in high blood glucose
-F-1,6-BP promotes PK
-ATP and alanine (indicate high energy status or low blood glucose level (starved state))

133
Q

Other sugars which can enter glycolysis

A

-Fructose, galactose and lactose.
> Fructose in liver: to DHAP or GAP
> Fructose in adipose tissue: to F-6P
> Galactose to G-6P

134
Q

Where is fructokinase expressed?

A

Only in the liver
> converts fructose to F-1P. (costs ATP)
> F-1P converted to glyceraldehyde and DHAP (F-1P aldolase)
> Glyceraldehyde ? GAP (triose kinase, costs ATP)

135
Q

Why is fructose more fattening than glucose?

A

The most regulated step: PFK1 is bypassed in the liver
> glycolysis cannot be stopped
> TCA cycle will stop when enough energy, conversion to fat

136
Q

Substrate pentose phosphate pathway (PPP)

A

Glucose-6-P

137
Q

Product PPP

A

Ribose-5-P (C5)

138
Q

Where does the PPP take place, and glycolysis

A

Both cytosol

139
Q

Function PPP

A

Production NADPH and Ribose-5-P (for RNA/DNA synthesis)

140
Q

Use of NADPH

A

Synthesis
-FA synthesis
-Cholesterol synthesis
-Neurotransmitter and nucleotide biosynthesis
Detoxification
-Reduction of oxidized glutathione (keep reduced environment, neutralize ROS)
-CYP enzymes

141
Q

Two stages PPP

A

-Oxidative phase
-Non-oxidative phase

142
Q

Oxidative phase PPP

A

-G6P > 6-PG (yield NADPH)
-6-PG > 6-PG lactone
-6-PG lactone > Ribulose-5-P (yield NADPH and CO2)
> sum: G6P + 2 NADP+ + H2O > R-5-P + 2 NADPH + 2 H+ + CO2

143
Q

Regulation oxidative phase PPP

A

First step via NADP+ concentration
> G6P to 6-PG (glucose 6 phosphate dehydrogenase)

144
Q

Non-oxidative phase PPP

A

Make C3,4,5,6,7 molecules from ribose-5-P (from ribulose-5-P, this conversion is oxidative)

145
Q

Link PPP and glycolysis

A

the nonoxidative phase can yield glycolysis intermediates
C5 (ribose-5-P) + C5 <=> C3+C7 (by transketolase)
C3+C7 <=> C6+C4 (by transaldolase)
C4+C5 <=> C6 + C3
Sum:
3 C3 (ribose-5-P) <=> 2 C6 (fructose-6-P) + C3 (glyceraldehyde-3-P)
> intermediates glycolysis

146
Q

Glucose fates in erythrocytes

A

NADPH is important to reduce oxidative stress
> 90% glucose to anaerobic glycolysis
> 10% to PPP

147
Q

Function glutathione

A

Reduce oxidative stress in reduced form.

148
Q

Reduced glutathione (GSH) reaction with ROOH (oxidative stress)

A

2 GSH (red) + ROOH > GSSG (condensed with disulfide bond, oxidized) + H2O + ROH
> Glutathione reductase reduces dimer GSSG back to monomers GDH using the electrons from NADPH from the PPP

149
Q

ROS in red blood cells

A

Cause hemolysis
> when defect glucose-6-phosphate dehydrogenase (committed step PPP)

150
Q

The PPP is flexible: explain

A

Requirements of the cell determine which product is produced (NADPH, ribose-5-phosphate, ATP)

151
Q

HC06: Substrate TCA/Krebs cycle

A

Acetyl-CoA

152
Q

Roads to acetyl-CoA

A

From: pyruvate, fatty acids, ketone bodies and some amino acids (and ethanol)

153
Q

Ketone bodies derived from

A

acetyl-CoA

154
Q

TCA cycle in the ..

A

mitochondrion

155
Q

Anaerobic glycolysis uses LDH (lactate dehydrogenase) to generate

A

NAD+, to keep the glycolysis and ATP synthesis running

156
Q

Each acetyl-CoA gives

A

3 NADH and 1 FADH2

157
Q

NADH type and ATP yield

A

Soluble cofactor yields 2.5 ATP

158
Q

FADH2 type and ATP yield

A

Prostethic group yields 1.5 ATP

159
Q

How many CO2 are released per TCA cycle

A

2 CO2
> conversion isocitrate to a-ketoglutarate
> conversion a-ketoglutarate to succinyl-CoA

160
Q

TCA cycle summary

A

Series redox reactions
> Oxidation acetyl group (C2) to two CO2 (acetyl-CoA is completely gone in the cycle and cannot be used for biosynthesis once in TCA cycle).
> harvest high energy electrons
> these are used for ATP synthesis

161
Q

Thermodynamics TCA cycle

A

Condensation reaction oxaloacetate with acetyl-CoA to citrate
Substrate level phosphorylation of GDP to GTP in conversion succinyl-CoA to succinate
two oxidative decarboxylations

162
Q

Which enzyme links glycolysis to TCA cycle. Why is this important?

A

The pyruvate dehydrogenase complex
> irreversible: regulated
> pyruvate to acetyl-CoA

163
Q

Oxidative decarboxylation of pyruvate by PDH

A

Three subunit enzymes
E1: Pyruvate dehydrogenase
- Pyruvate > CO2 couped to TPP > Acyl-TPP
E2: Pyruvate transacetylase
-Acyl-TPP > TPP coupled to Lip-S-S > acyl-lipoate and acyl-lipoate> Lip-SH-SH coupled to CoASH to acetyl-CoA.
E3: dihydrolipoyl dehydrogenase: Lip-SH-SH (no disulfide bond)> Lip-S-S (disulfide bond) coupled to FAD > FADH2 and FADH2 > FAD coupled to NAD+ > NADH

164
Q

What kind of molecule is TPP, the acyl carrier involved in the oxidative decarboxylation of pyruvate?

A

TPP: thiamine pyrophosphate (vitamin B1)

165
Q

Regulation TCA cycle most important point

A

The PDH complex
> inactivation: phosphorylation by kinase
> activation; dephosphorylation by phosphatase
> Muscle: high ATP/ADP, Acetyl-CoA and high NADH inhibit PDH
> Muscle: low ATP/ADP (much ADP) and pyruvate promote PDH

166
Q

Why is it important that ATP inhibits PDH

A

Conversion pyruvate to acetyl-CoA is irreversible and there is enough energy
> ability to still make glucose through gluconeogenesis

167
Q

Intermediate formed in condensation reaction oxaloacetate (C4) + acetyl-CoA (C2) + H2O > citrate (C6) + CoA

A

Citryl-CoA

168
Q

Adding TCA cycle intermediates

A

Anaplerosis
> more pyruvate used to keep the cycle going > more O2 uptake due to large amounts of NADH and FADH2 produced for oxidative phosphorylation

169
Q

Succinyl-CoA can be used for biosynthesis of … and this is an example of …

A

Porphyrins and heme
> cataplerosis, removal TCA intermediate

170
Q

Control points TCA cycle

A

Isocitrate dehydrogenase
> inhibited by ATP and NADH
> promoted by ADP
a-ketoglutarate dehydrogenase
> inhibited by ATP, succinyl-CoA and NADH

Medical Biochemistry and Pathophysiology (16 decks)

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