Mstn Ii - Lecture 27

Front 1

Symptoms of diabetic ketoacidosis:

Back 1

- hyperglycemia
- low bicarbonate
- acidosis
- ketonemia
- ketonuria
- water deficit
- potassium deficit
- high blood urea nitrogen

Front 2

starting materials for gluconeogenesis can be derived from:

Back 2

lactice acid or amino acids from the muscle

Front 3

3 highly exergonic reactions in glycolysis:

Back 3

1) hexokinase
3) phosphofructokinase-1
last) pyruvate kinase

- need to be bypassed in gluconeogenesis in order to get back to glucose.

Front 4

First bypass of gluconeogenesis:

Back 4

pyruvate kinase: pyruvate -> phosphoenolpyruvate (PEP)

- pyruvate (3carbon) is transported from the cytosol into the mito, just as it is transported for its conversion to acetyl-coa by pyruvate dehydrogenase for entry into the citiric acid cycle.

- addition of CO2 and hydrolysis of ATP, catalyzed by pyruvate carboxylase -> oxaloacetate (4carbon)

- biotin cofactor

Front 5

anaplerotic

Back 5

- filling up reaction of the liver, kidney, and adipocyte (glycogen neogenesis)
- increase citric acid cycle intermediates.
- stimulated by acetyl-CoA buildup, signaling that the oxaloacetate availability is the limiting factor inthe rate of the citric acid cycle

Front 6

Convert Oxaloacetate out of the mito:

Back 6

- needs to be reduced to malate
- meanwhile shuttle reducing potential from the citric acid cycle into the cytosol for the reverse of Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) reaction.

Front 7

PEP carboxykinase

Back 7

convert oxaloacetate -> phosphoenolpyruvate (PEP)

- use GTP as the phosphate donor
- oxaloacetate is decarb and phosphorylated

Front 8

malate dehydrogenase

Back 8

- oxidize malate to oxaloacetate in the cytosol
- NAD+ is reduced to NADH
- oxaloacetate is then converted to PEP

Front 9

Lactate dehydrogenase

Back 9

- used when pyruvate comes from lactate
- oxidize lactate dehydrogenase to form pyruvate in the cytosol
- produce NADH in the cytosol
- oxaloacetate produced int he mito matrix is converted to PEP directly in the matrix, and PEP is transported out into the cytosol.

Front 10

If pyruvate was formed from the oxidation of lactate and an NADH was formed in the cytosol:

Back 10

the oxaloacetate is converted into PEP in the mito (mito PEP caroxykinase), and PEP is transported back to the cytosol.

Front 11

If pyruvate was formed from alaine:

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- the oxaloacetate needs to be trasnported out of the mito matrix along with the reducing potential of an NADH via the reduction to malate
- malate is oxidized to oxaloacetate and NADH is formed in the cytosol.
- This oxaloacetate is converted to PEP by cytosolic PEP carboxykinase

Front 12

second bypass:

Back 12

Phosphofructokinase-1 (PKA-1)

fructorse-1,6-bisphosphate -> fructose 6 phosphate

catalyzed by fructose 1,6 bisphosphatase (FBPase)

Front 13

fructose 1,6 bisphosphatase

(FBPase)

Back 13

- F1BP -> F6P
- second bypass enzyme
- removes the C1 phosphate by hydrolysis
- inhibited by fructose-2,6-bisphosphate

Front 14

Third bypass:

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- lack of hexokinase

- final step of gluconeogenesis
- glucose 6-phosphate -> glucose
- C6 phosphate is removed by hydrolysis
- this hydrolysis rxn is catalyzed by glucose-6-phosphatase

Front 15

glucose 6 phosphatase

Back 15

converts glucose 6 phosphate to glucose when glucose is liberated from glycogen

catalyze the 3rd bypass of gluconeogenesis: glucose 6 phosphate -> glucose

Front 16

gluconeogenesis regulation is controlled by hormones in the live:

Back 16

catecholamines, glucagon, and insulin

Front 17

2 points of gluceoneogenesis regulation:

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- concentration of fructose 2,6 bisphosphate
- action of pyruvate kinase

Front 18

regulation of fructose 2,6 bisphosphate levels

synthesis:
breakdown:

Back 18

synthesis: phosphofructokinase-2 (PFK-2)

breakdown: fructose-2,6-bisphosphatase (FBPase-2)

both enzymes are part of a single bifunctional protein, which is regulated by phosphorylation by protein kinase A.

Front 19

action of PFK-2 and FBPase-2 is regulated by:

when dephosphorylated?
when phosphorylated?

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phosphorylation

when dephosphorylated: PFK-2 is activated -> fructose-2,6-bisphosphate is produced, and glycolysis proceeds
- promoted by insulin

when phosphorylated: FBPase-2 is activated, and gluconeoenesis proceeds.
- promoted by glucagon and catecholamine

Front 20

phosphorylation of PFK-2 and FBPase-2

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occurs though the increase in cAMP caused by glucagon and catecholamines.
- results in the activation of protein kinase A -> catalyzes the phosphorylation of the polypeptide.

Front 21

second level of control:

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level of pyruvate kinase

inhibition will cause a rapid reversal and lead to gluconeogensis

Front 22

pyruvate kinase inhibited by:

Back 22

allosterically by alanine and by glucagon stimulated phosphorylation (protein kinase A)

Front 23

buildup of alanine =

Back 23

need for gluconeogenesis

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glucagon stimulate

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gluconeogenesis

it wants to elevate blood-glucose levels

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energy of gluconeogenesis:

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is tightly coupled to the beta-oxidation of fatty acids

Front 26

beta-oxidation of fatty acids yield:

Back 26

acetyl-coA

aerobic oxidation of acetyl-CoA yields high levels of evergy needed to drive gluconeogenesis

Front 27

# of intermediates in the citric acid cycle can be only increased by:

Back 27

converstion of pyruvate to oxaloacetate by pyruvate carboxylase

or

degradation of amino acids to yield citric acid intermediates.

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speed of amino acids catabolism

Back 28

very slow compared to catabolism of other metabolic fuels

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during starvation:

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- dearth of citric acid cycle intermediates, slowing down oxidation of acetyl-coa.
- slow cycle causes the buildup of acetyl-coa, which leads to the production of ketone bodies.
- ketone bodies go into the blood stream to compensate for low blood glucose and provide metabolic fuel to the brain

Front 30

amino acids can be degraded into:

Back 30

citric acid cycle intermediates (glucogenic amino acids)

or

acetyl-coa or acetoacetate, which leads to the production of ketone bodies (ketogenic amino acids)

Front 31

First step in degradation:

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- deamination to yield the respective alpha-keto acids.
- the amino group is transferred to the alpha-keto acid alpha-ketoglutarate
- resulting in the production of glutamate

Front 32

transaminases

Back 32

catalyze deamination in the first step of amino acid degradation

rxns occur after glycogen stores have been depleted, and are catalyzed by aminotransferases

Front 33

alanine

Back 33

- nontoxic carrier of the nitrogen to the liver where the nitrogen is prepared for excretion by the synthesis of urea

Front 34

urea cycle

Back 34

conversion of nitrogen from protein to urea

takes place only in the liver.

Front 35

aminotransferases

Back 35

work by transferring the amino group from an amino acid to alpha-ketoglutarate, yielding an alpha-keto acid and glutamata

Front 36

pyridoxal phosphate (PLP)

Back 36

cofactor of aminotransferase

derived from Vit B6

Front 37

In muscle, nitrogen from amino acids are largely gathered in the form of:

Back 37

glutamate.

acceptor for this reaction is alpha-ketoglutarate.

amino group of glutamate is then trasnferred to pyruvate to give alanine. -> amino group is transferred back to alpha-ketoglutarate to give glutamate.

Front 38

glutamate dehydrogenase

Back 38

catalyze deamination of glutamate in mito.
- oxidative deamination producing alpha-ketoglutarate
- produce ammonium ions that are used in the urea cycle

- use both NAD+ and NADP+ as oxidizing agents

Front 39

Glutamine

Back 39

- non-toxic nitrogen carrier
- made from the addition of an amino group to glutamate by glutamine synthetase

Front 40

glutaminase

Back 40

liberates nitrogen by hydrolysis

liver mitochondria.