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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
Q

what is the mechanism stage for E2 subunits?

A

acetyl transfer from lipoamide to CoA-SH

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26
Q

what is the mechanism stage for E3 subunits?

A

oxidation of reduced lipoamide and reduction of NAD+ to NADH

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27
Q

what is the first step/reaction of the CAC?

A

oxaloacetate + acetyl-CoA –> citrate (achiral)

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28
Q

what is the first step/reaction of the CAC catalyzed by?

A

citrate synthase

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29
Q

what is the delta G of the citrate synthase reaction?

A

-31.4 kJ/mol

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30
Q

what is the intermediate of the citrate synthase reaction?

A

S-citryl-CoA

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31
Q

what is the second step/reaction of the CAC?

A

citrate <–> 2R, 3S isocitrate

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32
Q

what is the second step/reaction of the CAC catalyzed by?

A

aconitase

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33
Q

what is the intermediate of the aconitase reaction?

A

cis-aconitase

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34
Q

what is the delta G of the aconitase reaction?

A

approx. 0

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35
Q

what does the aconitase rxn utilize?

A

4Fe/4S cluster, Arg580, Asp/His diade, Ser642 residue

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36
Q

what is the third step/reaction of the CAC?

A

2R, 3S isocitrate –> alpha-ketoglutarate

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37
Q

what is the third step/reaction of the CAC catalyzed by?

A

isocitrate dehydrogenase

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38
Q

what is the intermediate of the isocitrate dehydrogenase reaction?

A

oxalosuccinate

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39
Q

what does the third step/reaction of the CAC signify?

A

1st release of CO2 and capture of NADH2 in the CAC

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40
Q

what is the delta G of the isocitrate dehydrogenase reaction?

A

approx. -20 kJ/mol

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41
Q

what is the fourth step of the CAC?

A

alpha-ketoglutarate + HS-CoS + NAD+ –> succinyl-CoA + NADH + CO2

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42
Q

what is the fourth step of the CAC catalyzed by?

A

alpha-ketoglutarate dehydrogenase

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43
Q

what is special/cool about alpha-ketoglutarate DH?

A

it’s mechanism is identical to PDH: same multiplicity of subunits, same 5 cofactors (TPP, lipoamide, CoA-SH, FAD, NAD+)

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44
Q

what is different about alpha-ketoglutarate DH compared to PDH?

A

the subunits are differently named
transsuccinylase vs. transacetylase

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45
Q

what occurs during the alpha-ketoglutarate DH reaction?

A

the 2nd NADH is generated and the 2nd CO2 is released (not from our initial acetyl group either)

46
Q

what is the delta G of the alpha-ketoglutarate DH reaction?

A

-40kJ/mol

47
Q

what is the fifth step of the CAC?

A

succinyl-CoA + Pi + GDP –> succinate + HS-CoA + GTP

48
Q

what is the fifth step of the CAC catalyzed by?

A

succinyl-CoA synthetase

49
Q

what is the delta G of the succinyl-CoA synthetase?

A

approx. 0

50
Q

after part 5 of the CAC (succinyl-CoA synthetase reaction), what has occurred?

A

2 carbons released as CO2, 2 electron pairs captured as NADH, 1 GTP (ATP) synthesized

51
Q

what is the sixth step of the CAC?

A

succinate + FAD –> fumurate (trans) + FADH2

52
Q

what is the sixth step of the CAC catalyzed by?

A

succinate dehydrogenase

53
Q

how is FAD bound to succinate dehydrogenase?

A

prosthetic group bound to SDH (FAD/FADH2 can’t leave the enzyme)

54
Q

what is the only membrane-bound enzyme of the CAC?

A

succinate dehydrogenase

55
Q

where is succinate dehydrogenase bound?

A

associated with the inner mitochondrial membrane

56
Q

what is succinate dehydrogenase also known as?

A

Complex II (a complex of respiratory electron transport system)

57
Q

what is the seventh step of the CAC?

A

fumarate <—> L-malate (water into reaction)

58
Q

what is the seventh step of the CAC catalyzed by?

A

fumarase

59
Q

what is the delta g of the fumarase reaction?

A

approx. 0

60
Q

what is noteworthy about fumarase?

A

it operates near catalytic perfection

61
Q

what is the eighth step of the CAC?

A

L-malate + NAD+ —> oxaloacetate +NADH + H+

oxaloacetate + NADH + H+ —-> L-malate + NAD+

62
Q

what is the eighth step of the CAC catalyzed by?

A

malate dehydrogenase

63
Q

what occurs during the malate dehydrogenase reaction of the CAC?

A

the 4th electron pair is collected for RET (3rd NADH)

64
Q

what is the delta G of the malate dehydrogenase reaction?

A

+29.7 kJ/mol

65
Q

what upregulates PDH and CAC?

A

relatively low energy charge… AKA

high [ADP] and [AMP]
low [ATP]
high [NAD+/NADH]

66
Q

what downregulates PDH and CAC?

A

relatively high energy charge… AKA

low [ATP] and [AMP]
high [ATP]
low [NAD+]/[NADH]

67
Q

Pyruvate —> acetyl-CoA

A

thermodynamically irreversible, metabolically irreversible in mammals

68
Q

after pyruvate is converted to acetyl-CoA, what are the options of C?

A

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
Q

what are the three inhibitors of PDH?

A

NADH, acetyl-CoA, ATP

70
Q

how does NADH inhibit PDH?

A

inhibits E3 subunits; outcompetes NAD+ in E3 active sites, so it can’t reoxidize lipoamide

71
Q

how does acetyl-CoA inhibit PDH?

A

inhibits E2 subunits; competes with CoA-SH… high acetyl-CoA will turn off process that generates a lot of acetyl-CoA

72
Q

how does ATP inhibit PDH?

A

allosterically inhibits E1 subunits; inhibition is enhanced by fatty acyl-CoA’s; marker for the fasting state (keeps PDH inactive)

73
Q

what can and cannot be used for gluconeogenesis??!!

A

acetyl-CoA cannot be used for gluconeogenesis; pyruvate can

74
Q

what is an activator of PDH?

A

AMP

75
Q

how does AMP activate PDH?

A

allosterically activates E1 subunits

76
Q

Can PDH be phosphorylated/dephosphorylated in mammals?

A

yes

77
Q

what subunits of PDH can be phosphorylated?

A

E1alpha subunits

78
Q

what are the three phosphorylatable sites on the E1alpha PDH subunits?

A

Ser246, Ser271, Ser 203

79
Q

what occurs when any of the three phosphorylatable E1alpha PDH subunit sites are phosphorylated?

A

inactivation of PDH subunits

80
Q

phosphorylated PDH

A

inactive

81
Q

dephosphorylated PDH

A

active

82
Q

what enzyme phosphorylates PDH?

A

pyruvate dehydrogenase kinase (PDK)

83
Q

what are the four isozymes of PDK?

A

PDK1, PDK2, PDK3, PDK4

84
Q

what are all isozymes of PDK activated by?

A

acetyl-CoA and NADH

85
Q

what are all isozymes of PDK inactivated by?

A

pyruvate

86
Q

where is PDK1 found?

A

pancreatic Beta cells and cardiomyocytes

87
Q

what is the target site of PDK1?

A

site 3 (Ser203)

88
Q

where is PDK2 found?

A

cardiomyocytes and hepatocytes

89
Q

what is the target site of PDK2?

A

site 1 (Ser246)

90
Q

PDK3

A

weak expression in most tissues

91
Q

where is PDK4 found?

A

cardiomyocytes, skeletal myocytes, hepatocytes, adipocytes

92
Q

what is the target site of PDK4?

A

site 2 (Ser271)

93
Q

what is PDK4 used/seen as?

A

long-term regulatory mechanism of PDH

94
Q

what increases PDK4 expression?

A

increase stress… increase fasting state —> produces glucocorticoids which increases expression of PDK4

95
Q

glucocorticoids

A

major regulator of expression (ex: cortisol)

96
Q

what decreases PDK4 expression?

A

insulin (increase/presence)

97
Q

what enzyme dephosphorylates PDH?

A

pyruvate dehydrogenase phosphatase (PDP)

98
Q

what are the two isozymes of PDP?

A

PDP1 and PDP2

99
Q

where is PDP1 found?

A

skeletal muscle

100
Q

what is PDP1 activated by?

A

Ca2+ (direct response to muscle contraction)

101
Q

where is PDP2 found?

A

hepatocytes, adipocytes, cardiomyocytes

102
Q

what activates PDP2?

A

insulin (due at least in part to the activity of protein kinase B)

103
Q

T or F: PDP2 is at the level of expression

A

true

104
Q

what are PDP1 and PDP2 both activated by?

A

Mg2+ (connection to energy charge)

105
Q

when is Mg2+ sequestered and unavailable to activate PDP1 or PDP2?

A

high [ATP]
low [ADP] and [AMP]

106
Q

when is Mg2+ released and available to activate PDP1 and PDP2?

A

low [ATP]
high [ADP] and [AMP]

107
Q

what are the three activators of isocitrate dehydrogenase?

A

ADP, NAD+, Ca2+

108
Q

what are the two inhibitors of isocitrate dehydrogenase?

A

NADH and ATP

109
Q

what are the two inhibitors of alpha-ketoglutarate DH?

A

NADH (E3s), succinyl-CoA (E2s), and ATP (allosteric control of E1s)

110
Q

what activates alpha-ketoglutarate DH?

A

AMP (allosteric control of E1s)

111
Q

what does regulation of alpha-ketoglutarate DH do?

A

preserves S-C structure for Glu, Gln, Arg, Pro biosynthesis

112
Q

what can glutamine (Glu) be used for?

A

biosynthesis of pyrimidine and purine

Biochemistry II (4 decks)

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