Glycolysis and Pyruvate Dehydrogenase (Biochem) Flashcards
1
Q
in which cells does glycolysis occur?
A
- glycolysis occurs in all cells
- in RBC, glycolysis represents the ONLY energy-yielding pathway available (bc they don’t have mito)
2
Q
normal blood glucose in mM?
A
- normal = 4-6 mM
- 70-110 (or 60-100) mg/dL
3
Q
Why do we give Potassium Chloride to a patient in DKA?
A
- because we’re also giving insulin, and insulin causes K to be absorbed by the cells.
- Insulin causes Potassium to shift into the cells thereby decreasing the extracellular K level.
- That’s why insulin is used in the treatment of hyperkalemia.
- Level of Potassium in the serum also affects insulin secretion from the pancreas.
- Because the beta cells have an ATP dependent K channel which, when closed, leads to retained K inside the beta cell which favors depolarization thereby enhancing Calcium mediated release of secretory granules.
- Therefore, in hyperkalemia more K will enter the beta cell and insulin secretion will increase
- and conversely in hypokalemia the K ions are more likely to leave the beta cell and so insulin secretion will decrease.
4
Q
the first steps in glucose metabolism in any cell are:
A
- transport across the membrane
- and phosphorylation by kinase enzymes inside the cell to prevent it from leaving via the transporter
5
Q
most of the carbs in food are in complex forms like:
A
- starch: amylose and amypectin
- disaccharides: sucrose and lactose
- only a very small amount of the total carbs ingested are monosaccharides
6
Q
What begins to digest carbs in the mouth?
A
- in the mouth, secreted salivary amylase randomly hydrolyzes the starch polymers to dextrin ( less than 8-10 glucoses)
- upon entry into the stomach, the acid pH destroys the salivary amylase
7
Q
What breaks down dextrin? and where does this occur?
A
- in the intestine, dextrin are hydrolyzed to the disaccharides maltose and isolates
- disaccharides in the intestinal brush border complete the digestion process
8
Q
Maltase function
A
Maltase cleaves maltose to 2 glucoses
9
Q
isomaltase function
A
isomaltase cleaves isomaltase to 2 glucoses
10
Q
lactase function
A
lactase cleaves lactose to glucose and galactose
11
Q
sucrase function
A
sucrase cleaves sucrose to glucose and fructose
12
Q
- how does glucose get into the mucosal cells?
- is this active or passive transport?
A
- the sodium/glucose transporter moves glucose into mucosal cells
- this is an Active Transporter
- glucose entry into most cells is concentration driven
- it is INDEPENDENT OF SODIUM!!!!!!!
13
Q
What is the normal concentration of glucose in peripheral blood?
A
4-6 mM or 70-110 mg/dL
14
Q
Where is the GLUT 1 transporter found?
- kinetics
A
- GLUT 1 and GLUT 3 mediate basal glucose uptake in most tissues, including brain, nerves and RBC
- Their high affinities for glucose ensure glucose entry even during periods of relative hypoglycemia
- at a normal glucose concentration, GLUT1 and GLUT 3 are at Vmax.
15
Q
- GLUT 2 is found where?
- kinetics?
A
- GLUT 2 is a low-affinity transporter, found in hepatocytes
- after a meal, portal blood = rich in glucose
- GLUT 2 captures the excess glucose primarily for storage
- when the glucose concentration drops below the Km for the transporter, much of the remainder leaves the liver and enters the peripheral circulation
- in the beta islet cells of the pancreas, GLUT 2 (along with glucokinase) serves as the glucose sensor for insulin release
- Bc both GLUT 2 and glucokinase have high Km values for glucose, glucose is transported and phosphorylated via 1st order kinetics (directly proportional to glucose concentration in the bloodstream)
16
Q
GLUT 4 translocation to the cell membrane in skeletal muscle is stimulated by??
A
- exercise
- this effect, which is INDEPENDENT OF INSULIN, involves a 5’ AMP-activated kinase
17
Q
Where is the GLUT 3 transporter found?
A
- GLUT 1 and GLUT 3 mediate basal glucose uptake in most tissues, including brain, nerves and RBC
18
Q
- Where is GLUT 4 found?
- How does it respond?
A
- GLUT 4 is in adipose tissue and muscle
- it responds to the glucose concentration in peripheral blood
- the rate of glucose transport in these 2 tissues is increased by insulin, which stimulates the movement of additional GLUT 4 transporters to the membrane
- decreased insulin decreases the # of plasma membrane GLUT 4 transporters by endocytosis of the transporter into cytoplasmic vesicles.
- increased insulin increases the # of plasma membrane GLUT 4 transporters through fusion of the cytoplasmic vesicles containing the membrane-bound GLUT 4 with the plasma membrane.
19
Q
What signals insulin release in the beta islet cells of the pancreas?
A
- the GLUT 2 transporter and glucokinase serves as the glucose sensor for insulin release from the beta islet cells of the pancreas
- insulin secretion by the pancreatic beta cells is biphasic
- glucose stimulates the first phase (within 15 mins) with release of preformed insulin
- the 2nd phase (several hours) involves insulin synthesis at the gene level
20
Q
GLUT 1:
- tissues
- Km, Glucose
- functions
A
- most tissues (ESP BRAIN and RBC)
- Km, glucose: approx 1 mM
- f(x): basal uptake of glucose
21
Q
GLUT 2:
- tissues
- Km, Glucose
- functions
A
- liver, pancreatic beta cells
- Km, glucose: approx 15 mM
- f(x): uptake and release of glucose by the liver beta cell glucose sensor
22
Q
GLUT 3:
- tissues
- Km, Glucose
- functions
A
- most tissues
- Km, glucose: approx 1 mM
- f(x): basal uptake
23
Q
GLUT 4:
- tissues
- Km, Glucose
- functions
A
- skeletal muscle, adipose tissue
- Km, glucose: approx 5 mM
- f(x): insulin-stimulated glucose uptake; stimulated by exercise in skeletal muscle
24
Q
Although basal transport occurs in all cells indepdently of insulin, the transport rate ____ in adipose tissue and muscle when insulin levels ____
A
Although basal transport occurs in all cells indepdently of insulin, the transport rate INCREASES in adipose tissue and muscle when insulin levels RISE
25
Why does the transport rate of glucose into muscle cells INCREASE when insulin levels increase?
- the transport rate of glucose into muscles increases when insulin levels increase bc:
- muscle stores excess glucose as glycogen
26
Why does the transport rate of glucose into adipose tissue INCREASE when insulin levels increase?
- the transport rate of glucose into adipose tissue INCREASES when insulin levels increase bc:
- adipose tissue requires glucose to form dihydroxyacetone phosphate (DHAP) which is converted to glycerol phosphate and is used to store incoming FA as TG
- TGL = 3 FA attached to glycerol.
27
insulin ____ PFK-2 in the liver by _____
insulin stimulates PFK-2 in the liver by dephospho rylation
28
What 3 enzymes in Glycolysis are rate-controlled and catalyze irreversible steps?
*Because of these 3 enzymes, Glycolysis is Irreversible, when the liver produces glucose, different reactions and therefore different enzymes must be used at these points!
1. Hexokinase (all tissues) aka Glucokinase (in liver)
- Glucose --> Glucose 6P
- Mg2+ cofactor; requires ATP --> ADP
- Glucose 6P downregulates
- insulin stimulates
2. PFK-1
- Fructose 6P --> Fructose-1,6 bis P
- ATP --> ADP
- AMP stimulates
- ATP, citrate inhibit/downregulate
3. Pyruvate Kinase
- Phosphoenolpyruvate (PEP) --> Pyruvate
- ADP --> ATP
- Fructose 1, 6 bis P is an allosteric activator of forward reaction (of pyruvate kinase)
29
Pyruvate Kinase Deficiency
| - Findings
- 2nd MC genetic deficiency that causes hemolytic anemia
- AR
- (#1 MCC = G6PD deficiency)
* Causes:
- chronic hemolysis --> hemolytic anemia
- increased BPG --> lower-than-normal O2 affinity of HbA
- no heinz bodies (heinz bodies are more characteristic of G6PD deficiency)
- results from a partial enzyme defect
30
Effects of 2,3 bisphosphoglycerate on the O2/Hb curve
- RBC have bisphosphoglycerate mutase which converts 1,3 BPG to 2,3 BPG.
- 2,3 BPG binds to the beta chains of HbA and decreases its affinity for oxygen
- (shifts Hb/O2 curve to the R. Normal R shifts allow for O2 to be unloaded in tissues)
- an abnormal increase in RBC 2,3-BPG might shift the curve far enough to the R that HbA is not fully saturated in the lungs
- 2,3-BPG doesn't bind well to HbF because HbF doesn't have a beta subunit.
* Summary:
- 2,3-BPG decreases O2 affinity for Hb
- 2,3-BPG increases O2 unloading
- 2,3-BPG regulates how RBC carries O2
- HbF has a higher affinity for O2 than maternal HbA
- this allows transplacental passage of O2 from mother to fetus
31
NAD(H) is made from
niacin (Vitamin B3)
32
Hexokinase/Glucokinase
- glucose entering the cells is trapped by phosphorylation using ATP
- Hexokinase is widely distributed in tissues
- glucokinase is only found in hepatocytes and pancreatic beta islet cells
33
Hexokinase
- where is it found
- Km
- inhibited by?
- found in most tissues
- low Km (0.05 mM in erythrocytes)
- inhibited by glucose 6P
34
What does Arsenate do?
- Arsenate inhibits conversion of glyceraldehyde 3P to 1,3 bisphosphoglycerate by mimicking phosphate in the reaction.
- this is the reaction catalyzed by Glyceraldehyde 3P dehydrogenase
- The arsenate-containing product is water labile, enabling glycolysis to proceed, but resulting in no ATP production
35
Glucokinase
- where is it found
- Km
- Induced by?
- found in hepatocytes and pancreatic beta islet cells
- (along with GLUT2 acts as the glucose sensor)
- High Km (10 mM)
- induced by insulin in hepatocytes
36
Phosphofructokinase-1 (PFK-1)
- PFK-1 is the rate-limiting enzyme and main control point of glycolysis
- catalyzes Fructose 6P --> fructose 1, 6 bisP
- requires ATP
- PFK-1 is inhibited by ATP and citrate
- PFK-1 is activated by AMP
- F2,6 BP activates PFK-1
- insulin stimulates and glucagon inhibits PFK-1 in hepatocytes by an indirect mechanism involving PFK-2 and fructose 2,6 bisP
- in liver, PFK-1 is stimulated by Fructose 2,6 bisP, so the liver can make FA
37
Phosphofructokinase-2 (PFK-2)
- Fructose 6P --> Fructose 2,6 bisP
- only in liver
- insulin activates PFK-2 via the tyrosine kinase receptor and activation of protein phosphatases
- F2,6 BP activates PFK-1
- Glucagon inhibits PFK-2 via cAMP dependent protein kinase
- low levels of F2,6 BP inhibits PFK-1
38
RBC pathways
- Glycolysis (can only use glucose as fuel)
- hexose monophosphate shunt: antioxidant NADPH
- cation transport
- MetHb --> Hb (needs NADH)*
* in RBCs, 1/2 to 1% of Hb is Fe3+ and NADH reduces Fe3+ to Fe2+
39
What causes coagulation necrosis in an MI?
- during ischemic episodes the lack of O2 forces cells to rely on anaerobic glycolysis
- this increases production of lactic acid
- the increased intracellular acidosis can cause proteins to denature and precipitate, leading to coagulative necrosis
40
Glycolysis (summary)
- cytoplasmic process
- converts 1 Glucose into 2 Pyruvates
- releases energy captured in 2 substrate-level phosphorylations and one oxidation reaction
41
Glyceraldehyde 3P Dehydrogenase
- catalyzes an oxidation and addition of inorganic phosphate to its substrate
- results in the production of a high-energy intermediate 1,3 bisphosphoglycerate (1,3 BP glycerate)
- reduces NAD to NADH
- if oxidation is aerobic, the NADH can be deoxidized (indirectly) by the mitochondrial ETC , thus providing energy for ATP synthesis by oxidative phosphorylation
42
3-Phosphoglycerate Kinase
- transfers the high-energy phosphate bond from 1,3 BP glycerate to ADP = SUBSTRATE-LEVEL Phosphorylation
- reaction: 1,3 BP glycerate + ADP --> 3P glycerate + ATP
- substrate-level phosphorylations are NOT dependent on O2 and are the only means of ATP generation in anaerobic tissue
43
Pyruvate Kinase
- last enzyme in aerobic glycolysis
- catalyzes a substrate-level phosphorylation reaction by transferring a phosphate from PEP to ADP.
- Reaction: PEP + ADP to Pyruvate + ATP
- activated by fructose 1,6 BP from the PFK-1 reaction (feed-forward activation)
44
Lactate Dehydrogenase
- only used in anaerobic glycolysis
- reoxidizes NADH to NAD, replenishing the oxidized coenzyme for glyceraldehyde 3P dehydrogenase
- w/o mitochondria and O2, glycolysis would stop when all the NAD had been reduced to NADH.
- by reducing pyruvate to Lactate and oxidizing NADH to NAD, LDH prevents this from happening.
- in aerobic tissues, lactate does not normally form in significant amounts
- the resulting acidosis generated by anaerobic glycolysis can cause proteins to denature and precipitate, leading to coagulation necrosis
45
Important intermediates of glycolysis
1. DHAP (dihydroxyacetone phosphate) is used in liver and adipose tissue for TG synthesis
- DHAP --> Glycerol 3P (which is used for TGL synthesis and electron shuttle)
2. 1,3 BPG and PEP are high-energy intermediates used to generate ATP by substrate-level phosphorylation
46
Steps where Substrate-level phosphorylation occurs in Glycolysis
1. phosphoglycerate kinase converts 1,3 BP glycerate + ADP to 3P glycerate + ATP
2. Pyruvate Kinase converts PEP + ADP to Pyruvate + ATP
- substrate-level phosphorylations are NOT dependent on O2 and are the only means of ATP generation in anaerobic tissue
47
Anaerobic glycolysis yields
2 ATP/glucose by substrate-level phosphorylation
48
Aerobic glycolysis yields
2 ATP/glycose + 2 NADH/glucose that can be utilized for ATP production in the mitochondria (oxidative phosphorylation)
- however: the inner mitochondrial membrane is impermeable to NADH.
- so, cytoplasmic NADH is deoxidized to NADH and delivers its electrons to one of 2 electron shuttles in the inner membrane:
1. Malate Shuttle: the electrons are passed to mitochondrial NADH and then to the ETC
2. Glycerol Phosphate Shuttle: electrons are passed to mitochondrial FADH2
49
Malate Shuttle
- the inner mitochondrial membrane is impermeable to NADH.
- so, cytoplasmic NADH is deoxidized to NADH and delivers its electrons to one of 2 electron shuttles in the inner membrane.
- the malate shuttle produces:
- a Mitochondrial NADH and
- and yields approx 3 ATP by oxidative phosphorylation
50
Glycerol Phosphate Shuttle
- the inner mitochondrial membrane is impermeable to NADH.
- so, cytoplasmic NADH is deoxidized to NADH and delivers its electrons to one of 2 electron shuttles in the inner membrane.
- the GP Shuttle produces:
- a mitochondrial FADH2
- and yields approx 2 ATP by oxidative phosphorylation
51
Pathway for ATP production in RBC
RBC don't have mitochondria, so anaerobic glycolysis is the only pathway for ATP generation.
- yields 2 ATP/glucose
52
Adaption to high altitudes (low PO2) involves
- increased respiration
- respiratory alkalosis
- lower P50 for hemoglobin (initial)
- increased rate of glycolysis
- increased [2,3-BPG] in RBC (12-24 hrs)
- Normal P50 for Hb restored by the increased level of 2,3-BPG
- increased Hb and hematocrit (days-weeks)
* Respiration reaction: CO2 + H2O --> H2CO3 --> H+ + HCO3-
- if you decrease the CO2 you'll decrease the amount of H+ produced
- therefore, at higher altitudes, and increased respiration --> you have an increased pH
* 2,3-BPG doesn't mind to HbF because HbF doesn't have a beta subunit.
53
Pyruvate Kinase Deficiency
| - pathophysiology
- RBC has no mitochondria and is totally dependent on anaerobic glycolysis for ATP
- in PKD, the decrease in ATP causes the RBC to lose its characteristic biconcave shape
- this signals destruction of RBC in spleen
- Also, decreased ion pumping by Na+/K+ ATPase results in loss of ion balance
- -> osmotic fragility --> swelling and lysis
54
Lactase Deficiency (after ingestion of lactose)
- Sx
- WHY does this occur?
- Dx
- Tx
- Sx: diarrhea, bloating, cramps
- bacteria have no O2, so they get rid of electrons by producing CH4 and sulfur compounds and small organic acids
- the acids are osmotically active and result in the movement of water into the intestinal lumen
- Dx: positive H-breath test after an oral lactose load
- Tx: dietary restriction of milk/milk products (except unpasteurized yogurt, which contains active lactobacillus) or by lactase pills
55
What is the mechanism by which Galactose causes cataracts?
- Reaction:
1. Lactose --> glucose + galactose
2. if galactose accumulates, it moves out of the blood and deposits in the lens of the eye
3. There it is converted to galactitol by Aldose reductase.
- when making galactitol, all C have an OH group. so it gets trapped in the lens and can't leave
- if galactitol is trapped in the lens it causes swelling and cataracts (osmotic damage)
- Cataracts: opacification of lens affection vision.
- painless, often bilateral
56
Galactokinase Deficiency
1. Galactokinase deficiency
- galactokinase converts galactose to galactose 1P
- requires 1 ATP
- less severe than Galactose 1 -P uridyltransferase deficiency
57
Galactose 1 -P uridyltransferase deficiency
- What reaction should this enzyme catalyze
- Sx and Tx
- Converts Galactose 1P to Glucose 1P
- more severe than Galactokinase deficiency bc you not only develop galactosemia, but Galactose 1-P also accumulates in the liver, brain and other tissues
- cataracts early in life
- vomiting, diarrhea following lactose ingestion
- failure to thrive
- Swelling in the brain: hypotonia, lethargy, mental retardation
- liver damage (acute liver injury can cause vomiting)
- hyperbilirubinemia (bc liver = site of bilirubin conjugation)
- bleeding problems (results from liver damage)
- Tx: avoid galactose, including breast milk. Give lactose-free formula supplemented with sucrose
58
Cataracts
1. Def
2. Risk Factors
1. Cataracts: opacification of lens affection vision.
- painless, often bilateral
2. Risk Factors: age, smoking, excessive ethanol use, prolonged corticosteroid use, excessive sunlight, classic galactosemia, galactokinase deficiency, trauma, diabetes (sorbitol), infection (rubella)
59
What is the mechanism by which diabetics get cataracts?
1. Aldose reductase converts Glucose to Sorbitol
| 2. Sorbitol accumulates and causes osmotic damage = cataracts
60
Galactosemia
- AR
- results from a defective gene encoding either galactokinase or galactose 1-P uridyltransferase
- can be caused by over 100 heritable mutations
- 1/60,000 births
- Elevated blood and urine [galactose]
- can result in decreased glucose synthesis and hypoglycemia
- Sx begin around day 3 in a newborn and include hallmark cataracts.
- Jaundice and hyperbilirubinemia do not resolve if the infant is treated with phototherapy
- in the galactosemic infant, the liver (site of bilirubin conjunction) develops cirrhosis
- Severe bacterial infections are common (i.e. E. coli sepsis) in untreated infants
- failure to thrive, hypotonia, lethargy and mental retardation are other common features
- Ex) 2wk old infant who was being breast-fed returned to hospital bc frequently vomited, had persistent fever, and looked yellow since birth.
- has early hepatomegaly and cataracts
61
1 day old female delivered at 34 weeks due to intrauterine growth retardation developed progressive respiratory failure that required intermittent mechanical ventilation.
- her blood glucose was 13.4 mM and increased to 24.6 mM.
- insulin administered to normalize her glucose
- no C-peptide was detectable
- her parents were 2nd cousins
- both had symptoms of mild diabetes controlled by diet alone
- genetic studies showed missions mutation (Ala378Val) in the glucokinase gene
- the parents were heterozygous and the infant was homozygous for the mutation
- This infant has Glucokinase deficiency
- remember: Glucokinase phosphorylates Glucose, trapping it the liver. It is necessary for glycolysis to occur
- near-complete deficiency of glucokinase activity is assoc with permanent neonatal T1 diabetes
- Some mutations in the glucokinase gene alter the Km for glucose (although not in this patient)
- those mutations that DECREASE Km (increasing its affinity for glucose) result in hyperinsulinemia and hypoglycemia
- Conversely, mutations that INCREASE the Km (decreasing its affinity for glucose) are associated with some cases of maturity-onset diabetes of the young (MODY)
62
Why does a high fructose drink supply a quick source of energy in both aerobic and anaerobic cells?
Because dihydroxyacetone phosphate and glyceraldehyde (the products of fructose metabolism) are DOWNstream from the key-regulatory and rate-limiting enzyme of glycolysis (PFK-1)
63
Fanconi Syndrome
- renal proximal tubule defect (Fanconi): where glucose, amino acids, uric acid, phosphate and bicarbonate are passed into the urine, instead of being reabsorbed.
- can be inherited or caused by drugs or heavy metals
64
TPP (Thiamine pyrophosphate) is made from
Thiamine (Vitamin B1)
65
Coenzyme A (CoA) is made from
pantothenate (Vitamin B5)
66
if you decrease the Km of an enzyme for a specific substrate you ____
- increase the affinity of that enzyme for that substrate
- ex) mutations that DECREASE the Km of glucokinase (increasing its affinity for glucose) result in hyperinsulinemia and hypoglycemia
- remember: Glucokinase phosphorylates Glucose, trapping it the liver
67
Hereditary Fructose Intolerence
- AR
- 1/20000
- due to defect in the gene that encodes aldolase B in fructose metabolism
- in the absence of the enzyme, fructose 1P accumulates in hepatocytes and in proximal renal tubules
- this traps inorganic phosphate in this substance, removing it from the phosphate pool
- the drop in phosphate levels prevents its use in other pathways, such as glycogen breakdown and gluconeogenesis
- eventually the liver (and kidney) becomes damaged due to accumulation of trapped fructose 1P
- ex) 4mo infant was breast-fed and developing normally. but when he was weaned mother began feeding him fruit juices. Within a few weeks the child became lethargic, yellow-skinned, and vomited frequently, and had frequent diarrhea.
- will find sugar in urine on testing, but the sugar won't react with glucose dipsticks
- Tx: exclude fructose and sucrose from diet. But complete exclusion of these sugars is difficult, and failure to correct the diet and prolonged fructose ingestion could eventually lead to a proximal renal disorder resembling Fanconi syndrome.
68
FAD(H2) is made from
riboflavin (Vitamin B2)
69
if you increase the Km of an enzyme for a specific substrate you ____
- DECREASE the affinity of that enzyme for that substrate
- ex) mutations that INCREASE the Km of glucokinase (decreasing its affinity for glucose) are associated with some cases of maturity-onset diabetes of the young (MODY)
70
Aldolase B (Fructose 1-Phosphate aldolase activity) deficiency
- Fructose 1-P accumulates in tissues and causes damage
- lethargy, vomiting
- liver damage (acute liver injury can cause vomiting)
- hyperbilirubinemia (bc liver = site of bilirubin conjugation)
- hyperuricemia (bc kidneys aren't working properly)
- renal proximal tubule defect (Fanconi): where glucose, amino acids, uric acid, phosphate and bicarbonate are passed into the urine, instead of being reabsorbed.
- aka hereditary fructose intolerence: occurs after learning from breast milk, i.e. 1yo previously healthy kid)
- sx are reversed after removing fructose and sucrose from diet
71
Cofactors and Coenzymes used by pyruvate dehydrogenase include
- Thiamine pyrophosphate (TPP) from the vitamin thiamine (Vitamin B1)
- lipoic acid
- coenzyme A (CoA) from pantothenate (vitamin B5)
- FAD(H2) from riboflavin (Vitamin B2)
- NAD(H) from niacin (Vitamin B3) (some may be synthesized from tryptophan)
- Pyruvate Dehydrogenase: Pyruvate --> Acetyl CoA
- Acetyl CoA inhibits pyruvate dehydrogenase
- Pyruvate Dehydrogenase is found in MITOCHONDRIA
72
Why does lactose deficiency increase as we age?
- bc as we age euchromatin is converted to heterochromatin
- Lactose deficiency = #1 gene disorder of all time
- 90% asians, 50% mexicans, also high in blacks
73
Why can high levels of galactose lead to cataracts but high levels of fructose don't?
- If you have high blood [fructose], no problem. You can just pee it out.
- Fructokinase deficiency is benign!
- Aldose reductase is an enzyme that usually reduces aldehyde group of aldoses
- Fructose is not an aldose sugar (has no aldehyde), so it's not a substrate for aldose reductase in the lens
* Fructokinase deficiency is benign!
74
Glycolysis occurs in the
Cytoplasm
75
- Alcoholics are deficient in ____
| - Sx of this deficiency
- Thiamine
- Ethanol inhibits absorption
- Sx: ataxia, nystagmus, opthalmoplegia, nystagmus, memory loss and confabulation, cerebral hemorrhage
- Wernicke-Korsakoff syndrome
- insufficient Thiamine (VB1) significantly impairs glucose oxidation, causing highly aerobic tissues (i.e. brain, cardiac muscle) to fail first.
- additionally, branched chain AA are sources of energy in brain and muscle
- CHF may be a complication (wet beri beri) owing to inadequate ATP and accumulation of ketoacids in the cardiac muscle
76
What happens if you give glucose without thiamine?
- lactic acidosis
- glucose load will increase glycolysis but if you lack thiamine, phosphate dehydrogenase will not work,
- and cells will make lactate to regenerate NAD
- Remember: Thiamine = Vitamin B1
77
Pathophysiology of Wet Beri Beri
- CHF may be a complication (wet beri beri) owing to inadequate ATP and accumulation of ketoacids in the cardiac muscle
- insufficient Thiamine (VB1) significantly impairs glucose oxidation, causing highly aerobic tissues (i.e. brain, cardiac muscle) to fail first.
- additionally, branched chain AA are sources of energy in brain and muscle
78
2 other enzyme complexes similar to pyruvate dehydrogenase that use thiamine are
- alpha-ketoglutarate dehydrogenase (TCA)
- Branched-chain ketoacid dehydrogenase (metabolism of branched-chain AA)
- additionally, branched chain AA are sources of energy in brain and muscle
- Remember: Thiamine = Vitamin B1
79
GLUT 2
- Km
- location and function
- High Km
- High Km allows it to have first order kinetics; absorption directly proportional to [glucose] in bloodstream
- liver (storage)
- beta islets (glucose sensor)
80
GLUT 4
- Km
- location and function
- Lower Km
- insulin stimulated
- adipose and muscle
81
regulation of pyruvate dehydrogenase (PDH)
1. PDH is active when dephosphorylated by PDH phosphatase
- PDH phosphatase is activated by calcium (exercise increases intracellular Ca2+ --> activates PDH by activating PDH phosphatase)
2. PDH is INACTIVE when PHOSPHORYLATED by PDH kinase
- PDH kinase is inhibited by substrate (pyruvate and ADP i.e. during exercise, energy use)
- PDH kinase is activated by products (Acetyl CoA, NADH, CO2)
- an increased NADH/NAD+ ratio (seen when cell's need for reduced NADH is being met) --> decreases PDH activity by activating PDH kinase
