Bioenergetics Flashcards
(88 cards)
1
Q
Acetyl CoA is the activated form of ___
A
Acetate
2
Q
What are the 3 energy sources Acetyl CoA can be generated from?
A
(1) Carbs Glucose -> 2 Pyruvate -> 2 Acetyl CoA (2) Lipids TAG -> FAs -> Acetyl CoA (via B oxidation) Oxidation of ketone bodies -> Acetyl CoA (3) Proteins Breakdown into AAs -> Acetyl CoA
3
Q
___ form of PDC is active
A
Dephosphorylated
4
Q
___ form of PDC is inactive
A
Phosphorylated
5
Q
Where does phosphorylation occur in PDC?
A
Coenzyme TTP of E1 complex
6
Q
What are the 5 coenzymes of the PDC?
A
- Thiamine Pyrophosphate (TPP)
- Coenzyme A (CoA)
- Lipoic Acid
- Flavin Adenine Dinucleotide (FAD)
- NAD
7
Q
What vitamin is TPP derived from?
A
B1 (thiamine)
8
Q
What vitamin is CoA derived from?
A
B5 (panthothenic acid)
9
Q
What vitamin is Lipoic Acid derived from?
A
None
10
Q
What vitamin is FAD derived from?
A
B2 (riboflavin)
11
Q
What vitamin is NAD derived from?
A
B3 (niacin)
12
Q
What does the enzyme Pyruvate Dehydrogenase Kinase (PDK) do to PDC?
A
Phosphorylates it = inactive
13
Q
What does the enzyme Pyruvate Dehydrogenase Phosphatase (PDP) do to PDC?
A
Dephosphorylates it = active
14
Q
What are the 3 activators of PDK?
A
- Acetyl CoA
- NADH
- ATP
15
Q
What are the 4 inhibitors of PDK?
A
- Pyruvate
- CoA
- NAD
- ADP
16
Q
What are the 2 activators of PDP?
A
- Ca2+
- Mg2+
17
Q
What are the 2 direct inhibitors of the E1 complex of PDC?
A
- Acetyl CoA
- NADH
18
Q
In a phosphatase deficiency…
(1) PDC is always in ___ form
(2) Glucose -> ___ rather than Acetyl CoA
(3) Results in constant ___ acidosis
A
(1) phosphorylated (inactive!)
(2) Lactate
(3) Lactic Acidosis (high blood levels of lactic acid)
19
Q
What system is affected the most by a phosphatase deficiency?
A
Central Nervous System
20
Q
Intake of what AA should be restricted in a phosphatase deficiency?
A
Alanine
21
Q
What happens if there is insufficient oxygen in muscle cells for further oxidation of pyruvate?
A
NAD is regenerated from NADH by reduction of pyruvate to lactic acid via Lactate Dehydrogenase Enzyme
22
Q
What type of diet is recommended in a phosphatase deficiency?
A
Ketogenic
helps minimize pyruvate formation
23
Q
What are the 3 rate irreversible steps/enzymes of the CAC?
A
(1) Citrate Synthase
(2) Isocitrate Dehydrogenase
(3) α-Ketoglutarate Dehydrogenase
24
Q
What enzyme results in the formation of GTP in the CAC?
A
Succinate Thiokinase
25
What is the rate limiting step of CAC?
Isocitrate -> α-Ketoglutarate
| Isocitrate Dehydrogenase
26
Which enzyme in the CAC requires the same 5 coenzymes as the PDC to function?
α-Ketoglutarate Dehydrogenase
27
When cellular ATP levels are low, the activity of TCA cycle is ____
Increased
28
When cellular ATP levels are high, the activity of TCA cycle is ___
Decreased / Inhibited
| mitochondrial ETC inhibition
29
Anaplerotic Reacations
- "fill up" reactions
| - provide intermediates to replenish the TCA cycle
30
What are the two major anaplerotic reactions?
- Degradation of AAs (produces either TCA cycle intermediates or pyruvate)
- Carboxylation of pyruvate (ie synthesis of OAA by decarbox of pyruvate)
31
(1) Degradation of what 4 AAs replenish α-Ketoglutarate? (2) What molecule are the 4 AAs turned in to before they can replenish α-Ketoglutarate?
(1) Glutamine, Histidine, Arginine, Proline (GHAP) (Go Poke His Arse)
(2) Glutamate
32
(1) Degradation of what 4 AAs replenish Succinyl CoA? (2) What molecule are the 4 AAs turned in to before they can replenish Succinyl CoA?
(1) Threonine, Isoleucine, Methionine, Valine (TIM V)
(2) Propionyl CoA
(Thor Met Val Inside College Pub)
33
(1) Degradation of what 3 AAs replenish Fumarate?
(1) Phenylalanine, Aspartate, Tyrosine (PAT)
| Try Phucking ASaP
34
(1) Degradation of what AA replenishes OAA?
| (2) What molecule is the AA turned in to before it can replenish OAA?
(1) Asparagine
| (2) Aspartate
35
What is the path taken by Pyruvate through the CAC when it feeds into lipid synthesis?
Pyruvate -> Acetyl CoA -> Citrate -> Citrate -> Acetyl CoA -> FAs, Isoprenoids
36
What is the path taken by Pyruvate through the CAC when it feeds into glucose synthesis (gluconeogenesis)?
Pyruvate -> OAA -> Malate -> Malate -> OAA -> PEP ---> Glucose
37
What inhibits pyruvate carboxylase in PDC?
Insulin
38
What can succinyl CoA be used in?
Formation of Porphyrins ----> Heme
39
What can TCA intermediates be used in?
- Nucleotide bases
- Proteins
- Fatty acids
- Isoprenoids
- Heme groups
40
2-Oxoglutaric Aciduria (α-ketoglutaric acid)
- disorder of TCA cycle
- involves α-Ketoglutarate
- rare disorder with global developmental delay and severe neurological problems in infants
- characterized by metabolic acidosis, severe microcephaly, intellectual disability
- variable urine excretion of 2-oxoglutarate
41
Fumarase Deficiency
- disorder of TCA cycle
- characterized by severe neurological impairment, encephalomyopathy, dystonia, increased urinary excretion of fumarate/succinate/α-Ketoglutarate/citrate
- fatal outcome within first two years of life
- autosomal recessive disorder
- mutation in fumarase gene contains Q319E
42
Succinyl CoA Synthetase (SCS) Deficiency
- disorder of TCA cycle
- associated with mutations in two out of three subunits making up the enzyme
- mutations occur on genes SUCLA2 and SUCLG1
- unique disorder b/c it involves both the CAC (due to abnormal succinate metabolism) and the mitochondrial DNA (mtDNA) maintenance
- increased amount of TCA cycle intermediates in the urine of patients
43
What do the SUCLA2 and SUCLG1 genes encode?
The β subunit of the ADP forming SCS and the α subunit of SCS
44
What are Oncometabolites?
small molecules of normal metabolism; excessive accumulation of them leads to metabolic dysregulatioon
45
What are the two oncometabolites of the TCA cycle? Also are major oncometabolites in cancer pathogenesis.
- Citrate
| - 2-Hydroxyl Glutarate
46
Mitochondrial depletion syndrome is associated with:
- Profound hypotonia (decreased muscle tone)
- Progressive dystonia (involuntary muscle contractions)
- Muscular atrophy
- Severe sensory neural hearing impairment
47
(CITRATE ONCOMETABOLITES)
Excess citrate reduces activity of the mitochondrial isoform of ____ and results in a shift of the cells metabolism towards ____
- Pyruvate Dehydrogenase
| - Glycolysis
48
(CITRATE ONCOMETABOLITES)
Increased accumulation of citrate activates _____ which increases the production of acetyl CoA and malonyl CoA
Acetyl CoA Carboxylase (ACC)
49
(CITRATE ONCOMETABOLITES)
Increased Acetyl CoA and Malonyl CoA is directed towards increased synthesis of __ and ___
Lipids & Sterol
50
Citrate Oncometabolites
- citrate accumulation in the cell
- favors non-oxidative breakdown of glucose in the cells and promotes cancer growth
- gylcolysis favored
- increased accumulation of pyruvate so cells convert it to lactate in order to regenerate NAD for use in glycolysis
51
2-Hydroxy Glutarate Oncometabolites
- mutations of IDH1 and IDH2 (cystolic and mitochondrial forms of IDH)
- leads to accumulation of 2HG
- mutation occurs in conversion of α-KG to 2-HGs
- accumulation of 2-HGs leads to the malignant progression of gliomas
52
Role of Phosphoenolpyruvate Carboxykinase in Cancer
- promotes cancer cell growth and proliferation (esp in colorectal cancer)
- increases glucose and glutamine uptake in cancer cells and favors anabolic metabolism
53
Successful OxPhos must accomplish the following 3 key goals:
- Transfer electrons from NADH and FADH2 to O2
- Establish a proton gradient across the inner mitochondrial membrane and in intermembrane space (proton motive force)
- Synthesize ATP
54
Electrons flow from ___ standard redox potential (Eo) to ___ standard redox potential. (measure of electron affinity)
Low to high
55
Standard redox potential and standard free energy (G) are ___ related
inversely
56
In the ETC, electrons are pumped from the __ to the ___
- Matrix
| - Inner-mitochondrial space
57
Inner-mitochondrial membrane is ___ to H ions, protons, and hydroxyl ions.
Impermeable
58
What two factors constitute a proton-motive force to drive ATP synthesis by Complex V?
(1) pH gradient in intermembrane space
| 2) membrane potential ("membrane intactness"
59
What membrane bound protein in OxPhos catalyzes ATP synthesis?
Complex V
60
1 mole of ATP requires passage of __ H through complex V
4
| 3 protons going thru channel, 1 proton used by adenine nucleotide translocator
61
What portion of Complex V contains the proton channel? Fo or F1?
Fo
62
What portion of Complex V contains subunits that provide catalytic activity for the complex?
F1
63
What inhibits Complex V?
Oligomycin - disrupts the proton transport thru the channel by inhibiting Fo region
64
What are 3 consequences of inhibiting the transfer of electrons across the ETC?
- decrease in the pumping of protons (b/c less protons in intermemb space)
- decrease in the proton (H+) gradient
- inhibition of ATP synthesis
65
What are the 4 inhibitors of Complex 1 of the ETC?
- Rotenone
- Amytal
- Myxothiazol
- Piericidin A
66
What inhibits Complex 2 of the ETC?
- Malonate
67
What happens in ETC/TCA when there is a high ATP/ADP ration?
inhibits ATP synthase -> increases H+ gradient -> decreases electron transport and H+ pumping -> slows down TCA cycle -> decreases glycolysis -> decreases ATP concerntration
68
What happens in ETC/TCA when there is a low ATP/ADP ration?
activation of ATP synthase -> decreases H+ gradient -> increases electron transport and H+ pumping -> accelerates TCA cycle -> increases glycolysis -> increases ATP concentration
69
What are the two things OxPhos regulation is sensitive to?
- Oxygen
| - ATP/ADP ratio
70
___ production is the result of uncoupling Ox Phos from ATP synthesis
Heat
71
Brown Adipose Tissue
- very rich in mitochondria
- high expression of uncoupling protein (UPC1) which is found in inner mitochondrial membrane
- involved in thermogenesis
- uncoupling of Ox Phos from ATP synthesis occurs here
72
How does UCP1 generate heat?
It short-circuits the mitochondrial proton gradient which results in the energy from the proton gradient being released as heat as protons fall thru UCP1 to mitochondrial matrix
73
What binds to/activates UCP1?
Long Chain FAs
(bind to UCP1 which causes structural change in enzyme and forms UCP channels so protons can flow from intermemb space to matrix)
74
What happens when the proton gradient is disrupted?
- P ~ ADP uncouples from ETC
- protons reenter mitochondrial matrix from intermemb space
- TCA cycle and electron transfer to O2 are accelerated
- ATP synthase is inhibited (no ATP synthesis)
- heat generation
75
Free ___ mainly generated in the mitochondria
Radicals
76
What two enzymes play a role in neutralizing free radicals?
- Superoxide Dismutase (SOD)
| - Catalase
77
List 3 anti-oxidants
- Glutathione Peroxidase
- Vitamin E
- Vitamin C
78
What powers the mitochondrial membrane transport system?
Membrane Potential or Proton Gradient
79
Phosphate/OH- Antiport
- pumps OH- into intermembrane space
- pumps H2P04- into mitochondrial matrix
- driving force is pH gradient
80
Phosphate/Malate Antiport
- pumps malate into intermembrane space
| - pumps HP04 into mitochondrial matrix
81
ADP/ATP Antiport
- pumps ATP into intermembrane space
- pumps ADP into mitochondrial matrix
- driving force is pH gradient and membrane potential
82
Pyruvate/OH- Antiport
- pumps OH- into intermembrane space
| - pumps Pyruvate into mitochondrial matrix
83
Malate-Aspartate Shuttle
- reversible
- operates in the heart, liver and kidneys
- generates NADH into mito-matrix
- NADH enters ETC at Complex 1
- can form max of 3 ATP
84
Glycerophosphate-Shuttle
- irreversible
- operates in skeletal muscle and brain
- generates FADH2 in the inner mitochondrial membrane
- FADH2 enters ETC at CoQ
- can form max of 2 ATP
85
(MITOCHONDRIAL DISEASE)
| Luft's Disease
- dominant sxs: perspiration, increased fluid intake with normal urine volume, high daily caloric intake, stable body weight, asthenic (loss of strength), progressive weakness
- lab findings: increased BMR (signifies heat production)
- mitochondria from striated muscle: uncoupling of OxPhos, high levels cytochrome c oxidase, low levels of CoQ
- other findings: large accumulations of mitochondria with highly variable size
86
Two primary causes of Mitochondrial Disease
(1) defect in nuclear DNA (nDNA) encoding the mitochondrial proteins
(2) defect in mitochondrial DNA (mDNA)
87
Clinical Features of Mitochondrial Disease
- nervous system: seizures, ataxia, dementia, deafness, blindness
- eyes: ptosis, retinis pigmentosa with vision loss
- heart: cardiomyopathy
- skeletal muscle: weakness, fatigue, myopathy, exercise intolerance, loss of coordination and balance
- others: liver failure, pancreatic disease, DM
88
Metabolic Features of Mitochondrial Disease
- low energy production
- increased free radical production
- lactic acidosis
