Glycolysis and Pyruvate Dehydrogenase

Question 1

Why do the GLUT 1 and 3 have high affinity for glucose? How is the Km and velocity in normal concentration of glucose?

Answer 1

Ensure glucose entry even in hypoglycemia 
Low Km (1mM)
Vmax at Normal [glc] - basal uptake

Question 2

What senses the glucose level for insulin release?

Answer 2

GLUT 2 and glucokinase in B cells pancreas

Question 3

Why is GLUT 4 transporter insulin-dependent? Where are those GLUT?

Answer 3

• Induce exocytosis of cytoplasmic vesicles containing GLUT 4 ▶️ fusion with cell membrane
• muscle, adipose tissue

Question 4

What other stimuli cause translocation of GLUT 4? What mechanism involve?

Answer 4

Exercise - independent of insulin

Involves a 5’ AMP-activated kinase

Question 5

In term of kinetics what would be the effect of insulin in transport and “behavior” of GLUT 4?

Answer 5

⬆️ Vmax - work as an activator (more numbers of transporters)

Question 6

How the mucosal cells uptake the glucose? Wha type of transport is it?

Answer 6

Na/glucose transporter

Active transport

Question 7

Why ischemia leads in coagulation necrosis?

Answer 7

⬇️ O2 ▶️ ⬆️ NADH (somebody has to oxidate it, mitochondria couldn’t) ▶️ LDH ▶️ ⬆️ lactic acid ▶️ acidosis ▶️ denature and precipitate proteins ▶️ coagulation necrosis

Question 8

What is the only mean to produce ATP in anaerobic tissue?

Answer 8

Substrate-level phosphorylation (no O2 dependent) - ADP is directly phosphorylated to ATP using a high-energy intermediate

Question 9

What enzymes in glycolysis can make substrate-level phosphorylation and get ATP directly? What intermediates substrates uses?

Answer 9

3-phosphoglycerate kinase ▶️ 1,3-Biphosphoglycerate

Pyruvate kinase ▶️ PEP

Question 10

What is the cause of permanent neonatal type 1 Diabetes? What is the mechanism?

Answer 10

Near-complete deficiency of glucokinase activity

Can’t sense glucose correctly with GLUT 2 ▶️ no insulin releasing

Question 11

What can cause a mutation in glucokinase that increase and decrease its Km?

Answer 11

• ⬆️ Km ▶️ (decrease affinity for Glc) ▶️ maturity-onset diabetes of the young (MODY)
• ⬇️ Km ▶️ (increasing affinity for Glc) ▶️ hyperinsulinemia and hypoglycemia

Question 12

What is the difference between hexokinase and glucokinase?

Answer 12

• the tissue (most tissues vs hepatocyte and B-islet cell)
• Km (⬇️ hexokinase, ⬆️ glucokinase)
• regulation (glucose 6P [-] hexokinase, insulin [+] liver glucokinase)

Question 13

What inhibit and activate the PFK-1? What is the role of insulin and glucagon?

Answer 13

• ATP and Citrate (-) by energy production, “active krebs”
• AMP (+) by Exercise
• insulin ▶️ (+) PFK-2 (dephosphorylate) ▶️ ⬆️ fructose 2,6 BP (+)
• glucagon (-) PFK-2 (phosphorylate) ▶️ ⬇️ fructose 2,6 BP

Question 14

For what can be used dihydroacetone-P (DHAP)?

Answer 14

• by glycerol-3P DH ▶️ glycerol-3P:
• TGL synthesis in adipose and liver
• electron shuttle

Question 15

What is the effect of an abnormal elevation of 2,3 BPG?

Answer 15

• ⬇️ even more the affinity of Hb for O2
• oxygen dissociation curve for HbA - shift the curve far right
• HbA hot fully saturated in lungs

Question 16

Second most common genetic deficiency cause of hemolytic anemia, what is the first?

Answer 16

• pyruvate kinase deficiency

- first: glucose 6-P DH deficiency

Question 17

Characteristic of pyruvate kinase deficiency

Answer 17

Hemolytic anemia, ⬆️ 2,3 BPG, No Heinz bodies

Question 18

What causes hemolysis in pyruvate kinase deficiency?

Answer 18

• ⬇️ ATP ▶️ RBC lose biconcave shape ▶️ spleen destruction

- ⬇️ ion pumping by Na/K ATPase ▶️ loss ion balance ▶️ osmotic fragility ▶️ swelling and lysis

Question 19

What is mechanism that produces cataracts (hallmark) in galactosemia?

Answer 19

• ⬆️ Gal in blood ▶️ aldose reductase in lens of eye ▶️ ⬆️ galactitiol ▶️ osmotic damage

Question 20

Why galactosemia by gal 1P uridyltransferase deficiency is more severe than galactokinase deficiency (only cataracts)?

Answer 20

• accumulation of Gal 1-P in brain, liver, other tissues

Question 21

Other symptoms of galactosemia (meanly Gal 1-P uridyltransferase deficiency)

Answer 21

• Hypoglycemia
• Jaundice and hyperbilirrubinemia (not resolve with phototherapy)
• 3 day old
• cirrhosis
• vomiting and diarrhea
• Severe bacterial infections (E. coli sepsis)
• thrive, lethargy, hypotonia, mental retardation
• newborn screening heel pick test

Question 22

Cause and symptoms of hereditary fructose intolerance

Answer 22

• aldolase B deficiency ▶️ accumulation fructose 1-P in liver and renal proximal tubules
• lethargy, liver damage, Renal proximal tubule defect (resemble Fanconi syndrome), hyperbilirrubinemia, hyperuricemia, hypoglycemia, vomiting
  “Let’s Live in Rest, two hygh, sweat low”

Question 23

Based on the role of Pyruvate dehydrogenase, what is the consequence of thiamine deficiency? Common cause of it?

Answer 23

• Alcoholics ▶️ ⬇️ thiamine absorption
• wenicke-korsakoff syndrome (peripheral neuropathy and psychosis)
• Cerebral hemorrhage, Ophtalmoplegia, Memory loss, Ataxia, psychosis (confabulation) and Nystagmus ▶️ “COMA On brain and eyes”

Question 24

What is “wet beri beri”? Why does it occur?

Answer 24

• Congestive Heart Failure by Chronic prolonged thiamine deficiency (complication)
• ⬇️ ATP, ⬆️ accumulate ketoacids in cardiac muscle

Question 25

What mainly regulates the PDH, in what pathway is it important?

Answer 25

• acetyl-Coa

- prevents consumption of Pyruvate when is needed ▶️ to gluconeogenic pathway

Question 26

What can happen if you give a glucose solution alone (without thiamine) to an alcoholic?

Answer 26

• kill him/her
• PDH not working good by lack of thiamine ▶️ pyruvate accumulate ▶️ go to another pathways: LDH and transamination
• LDH ▶️ lactic acidosis ▶️ ⬇️ pH in brain ▶️ “Wernicke encephalopathy”