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Flashcards in Metabolism 3 Deck (28):
1

What are the general precursors and fates of acetyl CoA? Draw.

p 3 or slide 2

2

Where and how is pyruvate formed?

Show eq.

Pyruvate is formed from the oxidation of glucose in the cytosol

Glucose + 2 NAD+ -> 2 pyruvate + 2 NADH + 2 H+

3

Where and how is pyruvate oxidized to acetyl-CoA?

Show eq.

Pyruvate is oxidized to acetyl-CoA in the mitochondrial matrix via the action of pyruvate
dehydrogenase (PDH).

2 Pyruvate + 2 NAD+ + 2 CoA PDH> 2 NADH + 2 H+ + 2 Acetyl-CoA

4

Where and how are fatty acids oxidized to acetyl-CoA?

Fatty acids join to CoA in the cytosol and are oxidized to acetyl-CoA in the mitochondrial
matrix via beta-oxidation.

C-16 fatty acyl-CoA + 7 NAD+ + 7 FAD + 7 H2O + 7 CoA B-oxidation>
7 NADH + 7 H+ + 7 FADH2 + 8-Acetyl-CoA

5

What is coenzyme A?

the universal carrier of acyl groups

6

What does the oxidation of acetyl-CoA lead to?

The oxidation of Acetyl-CoA leads to the production of
NADH, FADH2, and GTP.

7

Draw an overview of the Citric Acid cycle.

P 5

8

It is important to make sure patients have optimal dietary intake and nutritional status.

If a patient has low citrate, cis-aconitate and isocitrate, what does this mean?

amino acid insufficiencies

a need for arginine, lipoic
acid, magnesium, or amino acid supplementation

9

It is important to make sure patients have optimal dietary intake and nutritional status.

If a patient has elevated alpha ketoglutarate, what do they need?

What if low ketoglutarate?

high - need for vitamins B1, B3, and B5.

low- have aa insufficiences and need alpha ketoglutarate

10

What if a patient has elevated succinate, fumarate, and malate? What is insufficient?

then they have a coenzyme Q10 insufficiency

11

What if a patient had elevated succinate?

low succinate?

insufficiency of coenzyme Q10, vitamin B2 and magnesium

low- low aa, specifically leucine and isoleucine

12

What if a patient had low fumarate?

low tyrosine and phenylalanine

13

What are the important outer membrane, inner membrane, and matrix enzymes for fatty acid metabolism?

What are the important inner membrane and matrix membrane CAC enzymes?

fatty acid metabolism:

outer membrane- fatty acyl-CoA synthetases
inner membrane- camitine: acyl-CoA transferase
matrix- fatty acid B oxidation system

CAC enzymes:
inner membrane: succinate dehydrogenase
matrix:
-citrate syntehase
isocitrate dehydrogenase
alpha ketoglutarate dehydrogenase
aconitase
fumarase
succinyl-CoA synthetase
malate dehydrogenase

14

Where are CAC enzymes located?

matrix and inner mitochondrial membrane

15

What provides the energy to synthesize ATP?

Show drawing diagram

The transfer of electrons from substrates to molecular
oxygen provides the energy to synthesize ATP

P 9

16

How many high energy phosphates are generated for each cycle of citric acid cycle?

Where do these come from?

10 high energy phosphates generated for each cycle of the citric acid cycle

reoxidation of 3 NADH at 2.5 ATP/NADH =7.5

reoxidation of 1FADH2 at 1.5 ATP/FADH2 =1.5

GTP (GTP + ADP ...GDP +ATP) =1

10 total

17

What is coarse control? What exerts the level of course control? Why?

What is the rate limiting factor? How does this relate to coarse control?

Coarse control is exerted by the level of ADP, because it is necessary to reoxidize NADH and FADH2 to regenerate NAD+ and FAD. The mitochondrial reoxidation of NADH or FADH2 is coupled to ATP synthesis from ADP. Consequently, the supply of ADP for ATP synthesis is usually rate limiting.

18

What is the supply of acetyl-CoA related to? (2 things)

The supply of Acetyl-CoA is related to the activity of pyruvate dehydrogenase and to the transport of fatty acids into the mitochondria The latter process is affected by the
availability of carnitine and the activity of carnitine acyl transferase-1/ carnitine palmitoyl
transferase-1

19

How are oxaloacetate levels affected?

What type of reactions replenish CAC intermediates?

Oxaloacetate levels are affected by biosynthetic pathways that deplete CAC intermediates;
anaplerotic reactions replenish CAC intermediates.

20

What exerts fine control?

Fine control is exerted by the allosteric effectors in the figure above (p. 10). Additional allosteric effectors may regulate a specific purified enzyme, but their physiological relevance has not been established.

21

Citric acid cycle provides intermediates for biosynthetic reactions. The TCA cycle is a source of
precursors for amino acid, fatty acid, and glucose synthesis.

Show this on a figure... what are precurosors for aa synthesis or fatty acid and sterol synthesis/ gluconeogensis?

p 11

citrate- fatty acid and sterol syntehsis

alpha-ketoglutarate- aa synthesis (to neurotransmitters)

succinyl CoA- heme synthesis

malate- gluconeogensis

oxaloacetate- aa synthesis

22

Citric acid cycle intermediates of the TCA cycles can be replenished by anaplerotic (filling in)
reactions. Which are these intermediates?

p 11

aa to glutamate for alpha ketoglutarate

valine and isoleucine to propionyl CoA to succinyl CoA

aa to fumarate

asparate to oxaloacetate

aa to pyruvate to acetyl CoA or oxaloacetate

23

What does the pyruvate dehydrogenase complex do?

What does it contribute to/ accomplish?

The pyruvate dehydrogenase complex contributes to transforming pyruvate into acetyl-
CoA by a process called pyruvate decarboxylation.

Acetyl-CoA may then be used in the TCA
cycle to carry out cellular respiration, so pyruvate dehydrogenase contributes to linking
the glycolysis metabolic pathway to the citric acid cycle and releasing energy via NADH.

24

Describe the pyruvate dehydrogenase complex. What is it made up of?

The pyruvate dehydrogenase complex is made up of multiple copies of several enzymes
called E1, E2, and E3, each of which performs part of the chemical reaction that converts
pyruvate to acetyl-CoA.

25

What is the most common form of PDH deficiency? How is it inherited?

The most common form of pyruvate dehydrogenase deficiency is caused by mutations in
the E1 alpha gene, and is inherited in an X-linked dominant manner; all other forms are
caused by various genes and are inherited in an autosomal recessive manner.

26

What do children with PDH deficiency exhibit clinically?

What does treatment include?

Children with pyruvate dehydrogenase deficiency exhibit elevated serum levels of lactate,
pyruvate and alanine, which produce a chronic lactic acidosis.

Treatment typically includes dietary supplementation with thiamine, carnitine, and lipoic
acids.

Some patients have been treated with dichloroacetate, an inhibitor of the protein kinase
subunit of pyruvate dehydrogenase complex.

27

Describe fumarase (Fumarase Hydratase) Deficiency or fumaric aciduria or Polygamist Down's.

How is it inherited?
What characterizes the disease symptomatically? What will urine contain

Describe the mutations and effect.

What are treatment options?

It is an autosomal receive metabolic disorder, which is extremely rare.

- The disease characterized by severe neurological impairment, encephalomyopathy and
dystonia developing soon after birth. Urine contains abnormally high amounts of fumarate
and elevated levels of succinate, alpha-ketoglutarate, citrate and malate.

- Mutations in the fumarase (fumarate hydratase) gene disrupt the enzyme's ability to convert
fumarate to malate, interfering with the function of this reaction in the citric acid cycle.

-The first mutation characterized in the gene for fumarase contains a glutamine (Gln or Q)
substituted for a glutamic acid (Glu or E) residue 319.

-There is no effective treatment available for fumarate hydratase deficiency. Nutritional
intervention (e.g., feeding gastrostomy) may be appropriate. Physical therapy and wheelchairs
can be useful for some individuals.

28

What is fluoroacetate?

fluoroacetate=rat poison

fluoroacetate is converted to fluorocitrate

FA is lethal in small dose; 0.2mg/kg of body weight rats

fluorocitrate inhibits aconitase and consequently it inhibits the CAC