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1
Q

Intermediates of the TCA cycle are used for :

A
  1. heme synthesis
  2. Gluconeogenesis
  3. Fatty acid synthesis
  4. AA synthesis
2
Q

One turn of the TCA cycle makes:

A

1- GTP
3- NADH
1- FADH2

3
Q

What are the 4 things that can all generate acetyl CoA for the TCA cycle?

A
  1. fatty acid- palmitate
  2. ketone body- acetoacetate
  3. pyruvate
  4. Ethanol
4
Q

Fatty acids and keytone bodies are ______ to acetyl-CoA

A

oxidized

5
Q

AA _____ can be converted to pyruvate and then oxidized to Acetyl-CoA

A

Alanine

6
Q

What enzyme converts pyruvate to acetyl-CoA at the end of glycolysis

A

Pyruvate dehydrogenase complex

7
Q

True or false:

conversion of pyruvate to acetyl-CoA will transfer a H to NAD to make NADH (first in TCA pathway)

A

True

8
Q

What are the inhibitors of pyruvate dehydrogenase?

A
  1. NADH (its own byproduct)

2. Acetyl-CoA (product)

9
Q

What are the activators of Pyruvate Dehydrogenase ?

A

Calcium

ADP

10
Q

The Pyruvate Dehydrogenase complex is part of the family of _____ ____ -_______

A

Alpha-keto-acid dehydrogenases

11
Q

What are the three main a-keto acid dehydrogenases associated with TCA cycle ?

A
  1. Pyruvate Dehydrogenase
  2. Alpha Keto-glutarate dehydrogenase
  3. Branched chain AA dehydrogenase (MSUD)
12
Q

What are the three subunits of of the Pyruvate dehydrogenase complex and what do they bind?

A
  1. E1= binds TPP
  2. E2= binds lipoate
  3. E3 = binds FAD
13
Q

What is the E1 subunit on pyruvate dehydrogenase called?

A

Pyruvate decarboxylase subunit

-binds Thyamine Pyrophosphate (2 P groups )

14
Q

What is the E2 subunit on pyruvate dehydrogenase called?

A

Transcylase subunit

-binds lipoate

15
Q

What is the E3 subunit called on the pyruvate dehydrogenase called?

A

Dihydrolipoyl dehydrogenase

-binds FAD

16
Q

What is the bond called that is created when pyruvate is converted to Acetyl CoA ?

A

High energy Thioester bond

O=C~SCoA

17
Q

When you convert Pyruvate to Acetyl CoA what 2 things are created as byproducts?

A

NAD to NADH

CoASH to CO2

18
Q

The creation of the high energy thioester bond of Acetyl CoA is coupled with what?

A

Reduction of NAD to NADH

19
Q

In step one of Pyruvate to Acetyl CoA, what occurs?

A

Pyruvate loses CO2 when A-keto acid DH acts on it and takes the acetyl group

20
Q

What is step oneafter the CO2 is lost from pyruvate?

A

Remaining 2 carbons are covalently bonded to Thyamine Pyrophosphate
-done by PDH

21
Q

What is step 2 after TPP is bound to Pyruvate that lost CO2

A

Requires lipomide

-2 Carbon unit is transfered and attaches to lipoic acid

22
Q

What happens after the 2 carbon unit (acetyl group) is transferred from the E1 unit with TPP (alpha-keto acid DH) to the E2 group of lipoic acid ?

A
  1. Acetyl group attached to thioester in Lipoic acid ( attached to trans Ac enzyme)
  2. -TPP regenerated for use again in step 1

3.Dihydrolipoyl transacetylase intermediate formed

23
Q

What is step 3 after the

Dihydrolipoyl transacetylase is formed?

A

Acetyl is attached to CoA group to make Acetyl-CoA (still high energy thioester bond)
PDH is used again to attach the acetyl to CoA

24
Q

What happens after the Acetyl-CoA is formed to the Transacetylase enzyme ?

A

Oxidized by FAD

-FAD is reduced to FADH2 which is then simultaneously oxidized by NAD as soon as FADH2 is made

25
Q

How does the NADH gets it H from the pyruvate dehydrogenase complex?

A

it oxidizes FADH2 after FAD has oxidized TransAcetylase enzyme back into the cycle for lipoic acid usage

26
Q

The Pyruvate Dehydration complex can be regulated through what two main ways?

A
  1. Covalent modification (phosphorylation will make it inactive)
  2. Allosteric regulation
27
Q

What is the enzyme that requires coenzyme FAD to oxidize lipoic acid for use again in the cycle?

A

Dihydrolipoyl Dehydrogenase

28
Q

Pyruvate Dehydrogenase complex is _____ when dephosphorylated in fed state.

A

active

29
Q

Pyruvate Dehydrogenase complex is inactivated when it is phosphorylated by what?

A

PDH Kinase

30
Q

When is the Pyruvate Dehydrogenase Kinase (PDH kinase) active to inactivate the PDH?

A

Levels of Acetyl CoA or NADH are high

31
Q

When is PDH kinase inhibited (not able to inactive Pyruvate Dehydrogenase)?

A

High levels of :
ADP
Pyruvate

32
Q

What 2 things at high levels can allosterically inactivate the Pyruvate Dehydrogenase complex while at the same time allosterically activate the PDH kinase?

A

Acetyl CoA

NADH

33
Q

What two things will allosterically activate the Pyruvate Dehydrogenase Complex?

A

Pyruvate

NAD+

34
Q

what does Pyruvate Dehydrogenase complex Phosphatase do ? who can activate the phosphatase?

A

removes the Phosphate from PDC to activate it

-insulin can activate the phosphatase

35
Q

What can allosterically activate the Phosphatase to make PDC active by removing the phosphorlyation ?

A

High Calclium levels

released during exercise

36
Q

Where is the Pyruvate Dehydrogenase Complex?

A

mitochondrial membrane

37
Q

Arsenic poisoning inhibits what two things?

A

Pyruvate Dehydrogenase complex and the ETC

38
Q

What are the products of the TCA cycle?

A
2 -CO2
1- CoASH
3- NADH
1- FAD(2H)
1- GTP
39
Q

Where does the TCA cycle occur?

A

In mitochondria

40
Q

What is the first intermediate created in TCA? what is its enzyme?

A

Citrate

Citrate synthase

41
Q

What does the Citrate synthase do ?

A

Adds the Acetyl group from Acetyl-CoA to Oxaloacetate to make Citrate

42
Q

What type of reaction does Citrate synthase cause?

A

Condensation reaction to combine oxaloacetate and acetyl-coA

43
Q

Where does the energy for the reaction that Citrate synthase causes come from?

A

the Thioester bond between CoASH and Acetyl - CoASH is released

44
Q

What is the second step intermediate created in TCA (after citrate)?

A

Aconitase will cause an isomerization reaction converting Citrate into Isocitrate

45
Q

What is the name of the second intermediate after Citrate?

A

Isocitrate

46
Q

The Aconitase facilitates _______ followed by _____ that results in bond rearrangement to form Isocitrate.

A

dehydration

rehydration

47
Q

Aconitase requires ______ to be active

A

Iron

48
Q

What is the third step intermediate:

Isocitrate is converted to ?

A

Alpha-ketoglutarate

first decarboxylation step where CO2 is released

49
Q

what enzyme will facilitate the decarboxylation of Isocitrate to Alpha-ketoglutarate?

A

Isocitrate Dehydrogenase

first major decarboxylation step in TCA

50
Q

Isocitrate Dehydrogenase requires ______ as a cofactor.

A

Magnesium

51
Q

What is the first regulated step in TCA cycle?

A

activity of Isocitrate dehydrogenase

52
Q

What is the 4th intermediate of the TCA cycle after alpha-ketoglutarate ?

A

Succinyl Co-A

53
Q

What enzyme will change alpha-ketoglutarate into Succinyl Co-A?

A

Alpha-keto glutarate dehydrogenase

54
Q

In the activity of Alpha-keto glutarate dehydrogenase, what occurs?

A

NAD is Reduced to NADH
CoASH is added to make Succinyl CoA
CO2 is released
(oxidative carboxylation reaction)

55
Q

What two things occur when Isocitrate dehydrogenase acts on Isocitrate to make Alpha-keto glutarate?

A

CO2 is release

NAD is reduced to NADH

56
Q

True or false:

Succinyl CoA has a high energy thioester bond

A

true - CoASH was added by Alpha-keto glutarate dehydrogenase

57
Q

Where does the energy to make GTP from addition of free phosphate to GDP come from ?

A

cleavage of high energy thioester bond on Succinyl coA and r

58
Q

What enzyme will convert Succinyl-CoA to Succinate and add a P to GDP?

A

Succinyl thiokinase

59
Q

What is Succinate converted to in the TCA cycle?

A

Fumarate

60
Q

What is the enzyme that converts Succinate to Fumarate?

A

Succinate Dehydrogenase

61
Q

Succinate Dehydrogenase is also _______ of the ETC.

A

Complex 2 of the ETC

62
Q

What will succinate Dehydrogenase do for the ETC as it converts succinate to fumarate for the TCA cycle?

A

reduce FAD to FADH2 for immediate use in the ETC as complex 2

63
Q

What will fumarate be converted to ?

A

Malate

64
Q

What will Malate be converted to in the TCA?

A

Oxaloacetate (high delta G (29.7) - needs energy to happen)

65
Q

What enzyme will convert Fumarate to Malate?

A

Fumarase (will cause hydration across double bond to make malate)

66
Q

What is the last step to make an NADH?

A

Enzyme Malate dehydrogenase reacting with Malate to make Oxaloacetate

67
Q

Why is the reaction that converts Malate to Oxaloacetate able to move forward when it has such a high delta G?

A

Oxaloacetate is kept at a reduced level in mitochondria

  • an intermediate for other pathways
  • will be used up all the time so the forces driving to equilibrium will allow reaction to occur
68
Q

What are the three steps that are regulated in TCA cycle the way that Pyruvate dehydrogenase is regulated ?

A
  1. Isocitrate dehydrogenase
  2. Alpha-keto glutarate dehydrogenase
  3. Malate dehydrogenase
69
Q

The oxidation reactions that convert pyruvate to CO2 are specifically catalyzed by _____ enzymes.

A

Dehydrogenases

70
Q

What will Citrate synthase be inhibited by ?

A

elevated levels of citrate

71
Q

What will high levels of ADP enhance in the TCA cycle?

A

Isocitrate Dehydrogenase activity

72
Q

What will High levels of NADH inhibit in the TCA cycle?

A

Isocitrate dehydrogenase

A-ketoglutarate dehydrogenase

Malate dehydrogenase

73
Q

WHat will high levels of Calcium enhance activity of in the TCA cycle?

A

Isocitrate dehydrogenase

Alpha-ketoglutarate dehydrogenase

74
Q

ADP is a signal of ____ energy in the cell.

A

low

75
Q

What other pathways does the TCA cycle play an important role in by creating intermediates for those pathways?

A
  1. Fatty acid synthesis
  2. AA synthesis
  3. Heme synthesis
  4. Gluconeogenesis
76
Q

What intermediate of TCA will contribute to Fatty acid synthesis?

A

Citrate

77
Q

What intermediate of TCA will contribute to AA precursors for Neurotransmitters through AA synthesis?

A

Alpha-ketoglutarate

78
Q

What intermediate of TCA will be used in Heme synthesis?

A

Succinyl CoA

79
Q

What intermediate of TCA will be used in Gluconeogenesis?

A

Malate

80
Q

What intermediates of TCA will be used for AA synthesis

A

Alpha-ketoglutarate

Oxaloacetate

81
Q

As intermediates are being pulled out of the TCA cycle for other reactions, _______ reactions will refill the intermediates for TCA usage.

A

Anapleurotic (anapleurosis)

82
Q

What is the anapleurotic reaction that will refill oxaloacetate?

A

Pyruvate carboxylase will change it back to Oxaloacetate

adds CO2 and uses ATP energy

83
Q

What does Pyruvate Carboxylase require as a cofactor to convert Pyruvate back to Oxaloacetate ?

A

Biotin (vitamin H)

84
Q

Biotin will bind CO2 as an intermediate and the activated CO2 is added to Pyruvate to form the carboxyl group of ______.

A

Oxaloacetate

85
Q

What is an allosteric activator of Pyruvate carboxylase?

A

Acetyl CoA

86
Q

IN the second anapleurotic reaction, Glutamate can be transaminated to _______ for the TCA cycle.

A

alpha-ketoglutarate

87
Q

What enzyme will change Glutamate to alpha-ketoglutarate

A

Glutamate dehydrogenase

direction of reaction will depend on cellular needs, easily reversible

88
Q

Valine and Isoleucine metabolism (BCAA) will eventually be converted into ______ that will be an anapleurotic reaction to refill _____.

A

Proprionyl Co-A

Succinyl CoA

89
Q

______ can be deaminated and refill oxaloacetate in the TCA cycle

A

Aspartate

90
Q

What are the main intermediates that are refilled in TCA cycle?

A

Oxaloacetate
Alpha-ketoGlutarate
Succinyl CoA
Fumarate (from AA)

91
Q

What are the two major anapleurotic reactions in TCA?

A

Pyruvate Carboxylase making Oxaloacetate

BCAA metabolized to make Succinyl CoA

92
Q

LDH will ______ pyruvate in combination with the coenzyme NADH which will be ______ in the reaction.

A

Reduce

Oxidize (lose its H)

93
Q

Decreased oxidation of NADH or FADH in ETC will result in _______ conversion of Pyruvate to Lactic Acid.

A

Increased

94
Q

High levels of NADH will regulate the TCA cycle by inhibiting the action of ________, _______, ______.

A

Isocitrate dehydrogenase

Alpha-ketoglutarate dehydrogenase

Malate dehydrogenase

95
Q

In ischemia (or inhibtor to ETS), the NADH will become elevated, and then the TCA will in result be inhibited due to _______ at increasing levels. The individual can then present with lactic acidosis.

A

NADH

96
Q

Inbetween what two intermediates is FAD reduced to FADH2 in TCA cycle? by what enzyme ?

A

Succinate to Fumarate

Succinate dehydrogenase

97
Q

What is an inhibitor of citrate synthase, isocitrate dehydrogenase, and alpha-ketoglutarate dehydrogenase ?

A

NADH

98
Q

Pyruvate dehydrogenase is an ____ linked trait.

A

X linked

99
Q

In pyruvate dehydrogenase deficiency , the venus lactate levels will remain ______ during fasted and fed states, and especially high after fed state.

A

High

greatly increased after meal of carbohydrates

100
Q

Many of the cofactors required for TCA cycle include:

A

TTP
FAD
Coenzyme A (CoASH)

101
Q

One molecule of Heme requires 8 ______ and 8 ________.

A

Glycine

Succinyl-CoA (comes primarily from TCA cycle)

102
Q

Heme is required for transport of oxygen in blood and what other process?

A

ETS - cytochrome oxidase, and many reducing reactions in ETS

103
Q

In the structure of Heme, there are 4 ______ rings joined by _____ bridges.

A

Pyrrole rings

Methenyl bridges

104
Q

Side chains of Heme on the rings can consist of what 4 groups that will be ordered to identify the type of heme?

A
  1. Acetyl
  2. Propionyl
  3. Methyl
  4. Vinyl

(ex: MVMVMPPM)

105
Q

What is the most common type of Heme?

What is the sequence?

A

Type III heme

MVMVMPPM
8 R groups - 1 for each pyrrole ring

106
Q

Synthesis of Heme starts with what two molecules?

A

Succinyl CoA and Glycine

107
Q

Heme synthesis pathway is regulated by feedback inhibition, meaning?

A

Heme can inhibit is own synthesis

only one regulatory step in pathway

108
Q

What is the name for the Enzyme that Heme will regulate its own synthesis through feedback inhibition that is blocked called?

A

Alpha-aminolevulinic synthase

109
Q

What is the final step in the heme synthesis?

A

Integrating the Fe (iron) into the Heme molecule ring - needed to funciton

110
Q

Glycine and Succinyl CoA will combine to make what in Heme synthesis ?

A

Alpha-Aminolevulinic acid

111
Q

What is released during the reaction caused by Alpha-aminolevulinic acid using Glycine and succinyl co-A as substrates?

A

CoASH and CO2

112
Q

What cofactor is required for the condesation of glycine with succinyl coA in heme synthesis ?

A

PLP (Pyridoxal phosphate) - B6

113
Q

In second step of heme synthesis you need 2 molecules of _________. It is a dehydration reaction where ___ molecules of water are released.

A

Alpha-Aminolevulinic acid (a-ALA)

2

114
Q

What is the enzyme that will combine two molecules of a-ALA through dehydration to form Porphobilinogen (a pyrrole ring)?

A

a-ALA dehydratase

115
Q

a-ALA dehydratase is not regulated but what can inhibit it?

A

Lead (high levels)

- stops heme synthesis

116
Q

The _______ are a series of diseases caused by deficiencies in the Heme synthesis pathway.

A

Porphyrias

- can present with any number of presentations

117
Q

Which reactions are irreversible in the TCA cycle?

A
  1. Isocitrate to a-ketoglutarate
  2. a-ketoglutarate to Succinyl Co-A
  3. Oxaloacetate+ Acetyl CoA to Citrate
118
Q

Which TCA intermediates have 6 carbons

A

Citrate

Isocitrate

119
Q

Which TCA intermediates have 5 Carbon

A

only Alpha-ketoglutarate

120
Q

Which TCA intermediates have 4 Carbons ?

A
Succinyl CoA
Succinate
Fumarate
Malate
Oxaloacetate
121
Q

Which TCA reactions have very strongly negative Delta G nots ?

A
  1. Acetyl CoA to Citrate
  2. Isocitrate to Alpha-keotglutarate
  3. Alpha-ketoglutarate to Succinyl CoA
122
Q

The reactions catalyzed by aconitase and malate dehydrogenase have ______ Delta G nots and are thermodynamically and kinetically _____.

A

positive

reversible

123
Q

Because _______ is rapid in both directions, equilibrium values for the concentration ratio of products to substrates is maintained, and the concentration of citrate is about ____ times that of isocitrate.

A

aconitase

20

124
Q

The accumulation of citrate instead of isocitrate facilitates transport of excess citrate to the cytosol where it can provide a source of acetyl-CoA for pathways such as ______ and ______.

A

Fatty acid synthesis

Cholesterol synthesis

125
Q

The large accumulation of citrate as opposed to isocitrate in TCA allows citrate synthase to decrease activity when flux through ______ _____ is decreased.

A

isocitrate dehydrogenase

126
Q

The malate is kept in a very large concentration compared to oxaloacetate (similar to citrate vs isocitrate funciton) so that in the liver during fasting, there is a net flux towards malate , so it can then be transported out of the mitochondria to provide a substrate for _______.

A

gluconeogenesis

127
Q

True or false:

Citrate synthase has no allosteric regulators

A

True - it is only regulated by the levels of citrate and avaliability of oxaloacetate

128
Q

At the concentration of isocitrate found in the matrix a small change in the concentration of ____ and _____can produce a large change in the rate of the isocitrate dehydrogenase reaction.

A

ADP (if avaliable increases rate)

NAD+(activator)
NADH (inhibitor)
ALLOSTERIC- powerful regulation

129
Q

The Km shifts to a much lower value for isocitrate dehydrogenase when ____ is avaliable as all of the subunits of the enzyme are in their active conformation.

A

ADP

130
Q

The alpha-ketoglutarate dehydrogenase complex, although not an allosteric enzyme, is product inhibited by what 3 things?

A

NADH
Succinyl-CoA (product)
GTP
(ADP indirectly if increased due to lack of NADH oxidation in ETS as it leads to NADH increase)

131
Q

In the liver, a decreased rate of isocitrate dehydrogenase will _____ citrate concentration, which stimulates citrate efflux to the cytosol .

A

increase

132
Q

In the brain , alpha-ketoglutarate intermediate is converted to ______ and then to ______ (GABA) as a neurotransmitter.

A

Glutamate

Gamma-aminobutyric acid (GABA)

133
Q

In skeletal muscle, Alpha-ketoglutarate is converted to _____, which is transported through the blood to other tissues.

A

Glutamine

134
Q

What does pyruvate carboxylase function as ?

A

major anaplerotic enzyme - catalyzes addition of CO2 to pyruvate to form oxaloacetate
-contains Biotin

135
Q

What does the pyruvate carboxylase interaction require to form oxaloacetate from pyruvate ?

A

Biotin
ATP and Magnesium
(forms carboxyl group by adding CO2 to pyruvate)

136
Q

As the concentration of oxaloacetate is depleted through the efflux of TCA cycle intermediates, the rate of the citrate synthase reaction decreases and acetyl-coA rises. Acetyl-CoA then activates _______ to synthesize more ______.

A

Pyruvate carboxylase

Oxaloacetate

137
Q

Alanine and Serine carbons can enter through _____ _____.

A

Pyruvate carboxylase

138
Q

In all tissues with mitochondria (except liver), oxidation of the two BCAA ____ and _____ to ______ forms a major anaplerotic route.

A

Isoleucine
Valine

Succinyl Co-A

139
Q

In the liver, other compounds (than isoleucine and valine) like methionine, threonine, and odd-chain-length or branched fatty acids also enter TCA cycle as ______.

A

Succinyl CoA

140
Q

In most tissues, glutamine is taken up fro the blood, converted to _____, then oxidized to ______, forming another major anaplerotic route.

A

glutamate

alpha-ketoglutarate

141
Q

TCA cycle can not be resupplied with intermdiates by ________ or ______ which forms only acetyl CoA.

A

even-chain-length fatty acid oxidation

ketone body oxidation

142
Q

In TCA cycle, two carbons are lost from citrate before _____ is formed, so there is no net conversion of _______ carbon to oxaloacetate.

A

Succinyl-CoA

Acetyl (carbon)

143
Q

Vitamin ____ deficiency reduces the activity of pyruvate dehydrogenase and the TCA cycle, severely restricting ATP generation.

A

B1 (Thiamine - used as Thiamine pyrophosphate in pyruvate dehydrogenase reaction to make Acetyl-coA)