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Biochemistry II > Exam 2 Pyruvate Dehydrogenase and the Citric Acid Cycle > Flashcards

Exam 2 Pyruvate Dehydrogenase and the Citric Acid Cycle Flashcards

1
Q

what are the goals of the PDH reaction?

A
  1. oxidize pyruvate (release CO2)
    • collect e- from this oxidation as NADH
  2. activate remaining acetyl group as a “high energy” thioester (acetate to acetyl-CoA)
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2
Q

what problem does PDH effectively deal with?

A

the alpha-decarboxylation of an alpha-keto acid which forms a highly unstable carbanion

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3
Q

what are the basics of the PDH structure?

A

3 different active sites, 5 types of subunits

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4
Q

how many E1 subunits are there?

A

240

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5
Q

dihydrolipoyl transacetylase

A

the E2 subunits and in some species E3 binding proteins of the PDH complex

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6
Q

how many dihydrolipoyl transacetylase subunits are there in PDH?

A

60

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7
Q

of the 60 dihydrolipoyl transacetylase subunits in PDH, which categories do the subunits fall into for MAMMALS?

A

48 E2s
12 E3 BPS

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8
Q

of the 60 dihydrolipoyl transacetylase subunits in PDH, which categories do the subunits fall into for GRAM POSITIVE?

A

all 60 are E2 subunits

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9
Q

dihydrolipoyl dehydrogenase

A

E3 subunits of PDH

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10
Q

how many dihydrolipoyl dehydrogenase subunits are in the PDH complex?

A

24

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11
Q

what is the structure term of the PDH complex?

A

dual-layered pentagonal dodecahedron

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12
Q

why is the PDH a dual-layered pentagonal dodecahedron?

A

core of E2 subunits and E3 BPs with an outer shell of E1s and E3s

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13
Q

what are the 5 cofactors required for PDH?

A

thiamin pyrophosphate (TPP), lipoate/lipoamide, coenzyme A, FAD, NAD+

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14
Q

TPP PDH cofactor

A

often used for alpha-decarboxylation of alpha-keto acids; provides an electron sink for an unstable electron pair

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15
Q

how is TPP bound to PDH?

A

E1 prosthetic group

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16
Q

lipoate/lipoamide PDH cofactor

A

derivatized to enzymes that use it via Lys side chain

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17
Q

how is lipoate/lipoamide bound to PDH?

A

E2 prosthetic group

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18
Q

Coenzyme A PDH cofactor

A

provides the thiol for our “high energy” thioester

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19
Q

how is coenzyme A bound to PDH?

A

transiently associated with enzymes that use it; used by E2 subunits (dihydrolipoyl transacetylase”)

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20
Q

FAD PDH cofactor

A

oxidation/reduction reactions; many reactions between FAD (fully oxidized) and FADH2 (fully reduced)

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21
Q

how is FAD bound to PDH?

A

E3 subunit prosthetic group

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22
Q

NAD+ PDH cofactor

A

oxidation/reduction reactions; “pyridine nucleotide” cofactors

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23
Q

how is NAD+ bound to PDH?

A

transiently associated with enzymes that use it

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24
Q

what is the mechanism stage for E1 subunits?

A

decarboxylation of pyruvate and acetylation of lipoamide

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25
what is the mechanism stage for E2 subunits?
acetyl transfer from lipoamide to CoA-SH
26
what is the mechanism stage for E3 subunits?
oxidation of reduced lipoamide and reduction of NAD+ to NADH
27
what is the first step/reaction of the CAC?
oxaloacetate + acetyl-CoA --> citrate (achiral)
28
what is the first step/reaction of the CAC catalyzed by?
citrate synthase
29
what is the delta G of the citrate synthase reaction?
-31.4 kJ/mol
30
what is the intermediate of the citrate synthase reaction?
S-citryl-CoA
31
what is the second step/reaction of the CAC?
citrate <--> 2R, 3S isocitrate
32
what is the second step/reaction of the CAC catalyzed by?
aconitase
33
what is the intermediate of the aconitase reaction?
cis-aconitase
34
what is the delta G of the aconitase reaction?
approx. 0
35
what does the aconitase rxn utilize?
4Fe/4S cluster, Arg580, Asp/His diade, Ser642 residue
36
what is the third step/reaction of the CAC?
2R, 3S isocitrate --> alpha-ketoglutarate
37
what is the third step/reaction of the CAC catalyzed by?
isocitrate dehydrogenase
38
what is the intermediate of the isocitrate dehydrogenase reaction?
oxalosuccinate
39
what does the third step/reaction of the CAC signify?
1st release of CO2 and capture of NADH2 in the CAC
40
what is the delta G of the isocitrate dehydrogenase reaction?
approx. -20 kJ/mol
41
what is the fourth step of the CAC?
alpha-ketoglutarate + HS-CoS + NAD+ --> succinyl-CoA + NADH + CO2
42
what is the fourth step of the CAC catalyzed by?
alpha-ketoglutarate dehydrogenase
43
what is special/cool about alpha-ketoglutarate DH?
it's mechanism is identical to PDH: same multiplicity of subunits, same 5 cofactors (TPP, lipoamide, CoA-SH, FAD, NAD+)
44
what is different about alpha-ketoglutarate DH compared to PDH?
the subunits are differently named transsuccinylase vs. transacetylase
45
what occurs during the alpha-ketoglutarate DH reaction?
the 2nd NADH is generated and the 2nd CO2 is released (not from our initial acetyl group either)
46
what is the delta G of the alpha-ketoglutarate DH reaction?
-40kJ/mol
47
what is the fifth step of the CAC?
succinyl-CoA + Pi + GDP --> succinate + HS-CoA + GTP
48
what is the fifth step of the CAC catalyzed by?
succinyl-CoA synthetase
49
what is the delta G of the succinyl-CoA synthetase?
approx. 0
50
after part 5 of the CAC (succinyl-CoA synthetase reaction), what has occurred?
2 carbons released as CO2, 2 electron pairs captured as NADH, 1 GTP (ATP) synthesized
51
what is the sixth step of the CAC?
succinate + FAD --> fumurate (trans) + FADH2
52
what is the sixth step of the CAC catalyzed by?
succinate dehydrogenase
53
how is FAD bound to succinate dehydrogenase?
prosthetic group bound to SDH (FAD/FADH2 can't leave the enzyme)
54
what is the only membrane-bound enzyme of the CAC?
succinate dehydrogenase
55
where is succinate dehydrogenase bound?
associated with the inner mitochondrial membrane
56
what is succinate dehydrogenase also known as?
Complex II (a complex of respiratory electron transport system)
57
what is the seventh step of the CAC?
fumarate <---> L-malate (water into reaction)
58
what is the seventh step of the CAC catalyzed by?
fumarase
59
what is the delta g of the fumarase reaction?
approx. 0
60
what is noteworthy about fumarase?
it operates near catalytic perfection
61
what is the eighth step of the CAC?
L-malate + NAD+ ---> oxaloacetate +NADH + H+ oxaloacetate + NADH + H+ ----> L-malate + NAD+
62
what is the eighth step of the CAC catalyzed by?
malate dehydrogenase
63
what occurs during the malate dehydrogenase reaction of the CAC?
the 4th electron pair is collected for RET (3rd NADH)
64
what is the delta G of the malate dehydrogenase reaction?
+29.7 kJ/mol
65
what upregulates PDH and CAC?
relatively low energy charge... AKA high [ADP] and [AMP] low [ATP] high [NAD+/NADH]
66
what downregulates PDH and CAC?
relatively high energy charge... AKA low [ATP] and [AMP] high [ATP] low [NAD+]/[NADH]
67
Pyruvate ---> acetyl-CoA
thermodynamically irreversible, metabolically irreversible in mammals
68
after pyruvate is converted to acetyl-CoA, what are the options of C?
carbon is committed to either: 1. generation of ATP via oxidative phosphorylation (oxidation via the CAC) 2. synthesis of fatty acids and other lipids
69
what are the three inhibitors of PDH?
NADH, acetyl-CoA, ATP
70
how does NADH inhibit PDH?
inhibits E3 subunits; outcompetes NAD+ in E3 active sites, so it can't reoxidize lipoamide
71
how does acetyl-CoA inhibit PDH?
inhibits E2 subunits; competes with CoA-SH... high acetyl-CoA will turn off process that generates a lot of acetyl-CoA
72
how does ATP inhibit PDH?
allosterically inhibits E1 subunits; inhibition is enhanced by fatty acyl-CoA's; marker for the fasting state (keeps PDH inactive)
73
what can and cannot be used for gluconeogenesis??!!
acetyl-CoA cannot be used for gluconeogenesis; pyruvate can
74
what is an activator of PDH?
AMP
75
how does AMP activate PDH?
allosterically activates E1 subunits
76
Can PDH be phosphorylated/dephosphorylated in mammals?
yes
77
what subunits of PDH can be phosphorylated?
E1alpha subunits
78
what are the three phosphorylatable sites on the E1alpha PDH subunits?
Ser246, Ser271, Ser 203
79
what occurs when any of the three phosphorylatable E1alpha PDH subunit sites are phosphorylated?
inactivation of PDH subunits
80
phosphorylated PDH
inactive
81
dephosphorylated PDH
active
82
what enzyme phosphorylates PDH?
pyruvate dehydrogenase kinase (PDK)
83
what are the four isozymes of PDK?
PDK1, PDK2, PDK3, PDK4
84
what are all isozymes of PDK activated by?
acetyl-CoA and NADH
85
what are all isozymes of PDK inactivated by?
pyruvate
86
where is PDK1 found?
pancreatic Beta cells and cardiomyocytes
87
what is the target site of PDK1?
site 3 (Ser203)
88
where is PDK2 found?
cardiomyocytes and hepatocytes
89
what is the target site of PDK2?
site 1 (Ser246)
90
PDK3
weak expression in most tissues
91
where is PDK4 found?
cardiomyocytes, skeletal myocytes, hepatocytes, adipocytes
92
what is the target site of PDK4?
site 2 (Ser271)
93
what is PDK4 used/seen as?
long-term regulatory mechanism of PDH
94
what increases PDK4 expression?
increase stress... increase fasting state ---> produces glucocorticoids which increases expression of PDK4
95
glucocorticoids
major regulator of expression (ex: cortisol)
96
what decreases PDK4 expression?
insulin (increase/presence)
97
what enzyme dephosphorylates PDH?
pyruvate dehydrogenase phosphatase (PDP)
98
what are the two isozymes of PDP?
PDP1 and PDP2
99
where is PDP1 found?
skeletal muscle
100
what is PDP1 activated by?
Ca2+ (direct response to muscle contraction)
101
where is PDP2 found?
hepatocytes, adipocytes, cardiomyocytes
102
what activates PDP2?
insulin (due at least in part to the activity of protein kinase B)
103
T or F: PDP2 is at the level of expression
true
104
what are PDP1 and PDP2 both activated by?
Mg2+ (connection to energy charge)
105
when is Mg2+ sequestered and unavailable to activate PDP1 or PDP2?
high [ATP] low [ADP] and [AMP]
106
when is Mg2+ released and available to activate PDP1 and PDP2?
low [ATP] high [ADP] and [AMP]
107
what are the three activators of isocitrate dehydrogenase?
ADP, NAD+, Ca2+
108
what are the two inhibitors of isocitrate dehydrogenase?
NADH and ATP
109
what are the two inhibitors of alpha-ketoglutarate DH?
NADH (E3s), succinyl-CoA (E2s), and ATP (allosteric control of E1s)
110
what activates alpha-ketoglutarate DH?
AMP (allosteric control of E1s)
111
what does regulation of alpha-ketoglutarate DH do?
preserves S-C structure for Glu, Gln, Arg, Pro biosynthesis
112
what can glutamine (Glu) be used for?
biosynthesis of pyrimidine and purine

Biochemistry II (4 decks)

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