Misc Flashcards
1
Q
What are Gags and what are the 6 GAGs
A
GAGs are glycosaminoglycans.
They are negatively charged and feature an acidic sugar with an N-acetylated amino sugar.
- Chondrion sulfate:
Glucuronic acid + N-acetylgalactosamine
-most abundant, found in cartilage, tendons and ligaments
-accumulates in Sly - Dermatan sulfate
Iduronic acid + GalNAC
(I do u) skin
skin, blood and valves. - Keratan Sulfate
Galactose and N-acetyl glucosamine
-found in cornea, connective tissues
-Morquio - Heparan sulfate: glucouronic acid + N-acetyl glucosamine.
membranes and cell surfaces - Heparin: Iduronic acid + glucosamine
- anticoagulant
- Hurler, Hunter, Sly, Sanfillipo - Hyaluronic acid: glucuronic acid and -acetylglucosamine. Lubricant, synovial fluid, vitreous, umbilical cord.
- no disease associated
2
Q
What is I cell disease?
similar to Pseudo-hurler polydystrophy
A
A deficiency in UDP-NAcglucosamine
due to a defect in the lysosomal enzyme N-acetylglucosamine phosphotransferase
They have ton of enzymes in the extracellular matrix that never reaches the lysosome.
You can diagnose the condition by measuring serum concentration of enzyme.
THey have course skin, thickening of skin and lips, belly is distended due to large liver and spleen, they have joint issues and cannot extend.
3
Q
Which GAG degradation issues result in accumulation of:
Dermatan sulfate
Heparan sulfate
Keratan sulfate
Chondroitin sulfate
A
Dermatan sulfate: Hunter, Hurler, Sly
Heparan sulfate: Hunter, Hurler, Sly, Sanfillipo.
Keratan sulfate
4
Q
What are azaserine
What is 6-Diazo-5-oxonorleucine (DON)
A
These two are analogs of glutamine. Glutamine is an important nitrogen donor for PRPP-amido transferase. Their action is the bind tightly and inhibit this committed step.
This is why they function as antibiotics.
5
Q
What are methotrexate and aminopterin and 5 flurouracil
A
It blocks the activity of Dihydrofolate reductase which is important in conversion of folate and dihydrofolate eventually to THF. THF is important for both synthesis of purines and pyrmaindines.
in purine sythesis is a crucial component of the PRA > IMF step.
These are both chemotherapeutic agents
methotrexate in a more specific sense also inhibits thymine synthesis as THF is a precursor of N5,N10 methylene THF which is a cofactor for Thymidylate synthase that converts dUMP to dTMP
For 5-Fluorouracil: this only binds to thymidylate synthase in the presence of THF. This blocks dUMP to TMP reaction yielding a thymineless death.
6
Q
What is Bactrim?
A
Bactrim is a mix of two drugs. Sulfonamides and Trimethoprim, BEST for bacterial treatment
Sulfonamide is an analog that inhibits synthesis of folic acid. In microorganism, PABA is made into folic acid. Well humans get folate from digestion so it is selective for bacteria
Trimethoprim binds more tightly to bacterial DHF reductase than mammalian making it also useful antibacterial agent.
7
Q
What is ribovarin and mycophelonic acid
A
Ribovarin prevents the synthesis of GMP. It does this by inhibintg IMP dehydrogenase which uses NAD+, takes a hydrogen making XMP.
Then glutamine and ATP come make GMP.
Mycophelonic acid is also an IMP dehydrogenase inhibitor. More specific for targeting T and B cells. It is used as an immunosupresent to prevent rejection of grafts.
8
Q
What happens in Lesch-Nyhan syndrome?
A
HGPRT deficiency
- x linked, recessive
- inability to salvage hypoxanthine or guanine.
Increases levels of PRPP, decreased IMP and GMP, relying on denovo purine synthesis
Excessive degradation leads to overproduction of uric acid.
Lesions of lips caused by self mutation, mental retardation, gout.
in Lesch Nyhan you mutilate Lips have elevated hypoXanthine, due to low hypoxanthine-guanine ribosyltransferase
9
Q
What is going on in SCID (severe combined immunodeficiency)
A
Genetic deficiency of Adenosine Deaminase which converts adenosine to inosine.
Severe bacterial viral deficiency.
There is a severe deficit of B and T lymphocytes.
There is a characteristic higher than normal dATP!
10
Q
What results from PNP deficiency (purine nucleoside phosphorylase)
A
What PNP (purine nucleoside phosphorylase) does is remove the ribose from either inosine or guanosine leaving hypoxanthine or guanine. This is the opposite of what is done in pyrmidine synthesis. Possibly a reversible reaction?
They are severely deficient in only T cells.
11
Q
What is allopurinol?
A
Allopurinol is an analog of hypoxanthine which inhibits xanthine oxidase which is the enzyme that both converts hypoxanthine to xanthine and then xanthine to uric acid.
Both xanthine and hypoxanthine are more soluble than uric acid, making it an effective treatment for gout.
PRPP levels also goes down as the body thinks you have produced usable nucleotide.
There is a second way it works, Alloxanthine, the product looks like a free base, together with PRPP makes an allopurinol-ribonucleotide which inhibits PRPP amidotransferase activity. lowering denovo synthesis.
12
Q
What happens in orotic aciduria?
A
UMP synthase contains two part, orotate phosphoribosyl transferase and orotidyldecarboxylase. Either can be mutated.
You will have megaloblastic anemia and excessive orotate in urine.
SO this is an important step in making UMP, a precursor for pyramidine synthesis. RBCS are ready to divide but don’t.
13
Q
How does acyclovir work?
A
It treats Herpes.
Viral thymidine kinase is sloppy compared to the one in humans. it takes the acyclovir, converting it into a chain terminating nucleotide. Viral TK will phosphorylate acyclovir while cellular TK doesnt
Acyclovir is preferentially incorporated into viral DNA because its DNA polymerase is less selective.
they know her guy is a cyclops
14
Q
What are the three important amino acid/keto acid pairs?
A
components of the TCA cycle, alpha-ketoglutarate, pyruvate and oxaloacetate.
- Transamination: moving amino group to alpha ketoglutarate forming glutamate.
- Glucose-alanine cycle: pyruvate to alanine
- Aspartate: oxaloacetate to aspartate.
15
Q
What is tetrahydrobiopterin?
A
It is a required cofactor for phenylalanine hydroxylase, the enzyme that converts phenylalanine to tyrosine and then to catecholamines
PKU is a defect in this enzyme resulting in high levels of phenyalanine and low levels of tyrosine.
Tetrahydrobiopterin is a cofactor of tyrosine hydroxylase. Tyrosine to DOPA.
16
Q
What three things are cofactors in the conversion of Norepinephrine to epinephrine?
A
- S-adenosyl methionine
- Methycobalamine - B12
- Folate
Ultimately it is a transfer of a methyl group.
17
Q
What is creatine?
A
Creatine is a storage form of energy.
The phosphate can be rapidly transfered to ADP to make energy
Creatinine is the derivate of creatine which is excreted.
If there is low levels of creatinine in the urine, that may mean muscle loss.
If there are high levels of creatinine in urine that points to kidney failure.
Creatine kinase adds the phosphate to creatine in the liver, and is transported to brain and muscle.
18
Q
a 4 month old boy is brought to your office by his parents. the child has been inconsolable for the past 2 weeks. On workup you note that the child has a neurodegeneration, hepatosplenomegaly, and a cerry red spot. What will accumulate in this patient
A
This is a description of Nieman Pick Disease. The answer is D. sphingomyelin.
19
Q
What metabolic things are only in liver and muscle
A
Liver:
- glucokinase
- fructose-6-phosphate/GKRP, fructose 1 phosphate
- PFK2 > stimulatory fructose 2,6 bisphosphate
- relies on insulin and glucagon for regulation as blood glucose is primary concern
- low NADH, favors lactate > pyruvate
- Glut2, not responsive to insulin, high Km
Muscle:
- hexokinase
- inhibited by product feedback (glucose 6 phosphate)
- relies on high energy compounds (ATP, citrate) and low energy compounds (ADP) for regulation
- high NADH which converts pyruvate to lactate.
- epinephrine activates glycolysis
- Glut4, responsive to insulin, low Km
20
Q
What is phenytoin?
A
It inhibits conjugase which is found on the vili of the jejunum.
Conjugase removes the glutamates because dietary folate is always polyglutamated.
It gets converted all the way to monglutamate and then it can be absorbed.
Conjugase can be compromised by sources of bowel irritation. Tropical sprue - bowel irritation from bacteria
Celiac Sprue: original irritation due to autoimmune response;.
21
Q
What is leucovorin (aka folinic acid)
A
There are many toxicities with methotrexate:
chemotherapeutic agent that adversely kills off rapidly dividing cells
-myelosuppression (bone marrow suppression leading to fewer RBcs, white blood cells and platelets
-mucositis - inflammation of mouth and gums, because there are rapidly dividing cells in mouth throat and stomach and intestines.
Leucovorin helps alleviate the block on THF formation.
1st of all methotrexate in cancer cells gets more polyglutamated too increasing its affinity for DHFR
2nd. leucoverin preferentially accumulates in normal cells, not really rescuing cancer cells.
22
Q
What is the SAM synthesis reaction
A
L-methionine + ATP forms SAM and 3 inorganic phosphates. SAM synthetase.
After donating a methyl group SAM becomes S-adenosyl homocysteine
Homocysteine levels are indirectly related to folate, B12 and B6.
23
Q
What does B12, have in common with amino acid degradation and odd cahin fatty acid degradation
A
Both converge at the product Propionyl coA. We know propionyl coA carboxylase is mediated with biotin into methylmalonyl coA.
B12 is a cofactor in the conversion of that into succinyl coA.
24
Q
What are the five set of symptoms that are involved in metabolic syndromes and of which having any 3 of them together classifies you as having metabolic syndrome?
A
Men & women
-waist > 40 in, waist > 35 in
- fasting TAGs >150 mg/dL for both
- HDL <40 mg/dL, <50 mg/dL
- blood pressure >130/85 both
- fasting glucose >110 mg/dl
25
What are three hypothesis for the role that visceral fat has in development of insulin resistance?
increase fatty acids indicates you ARE IN HUNGER> (glucagon increases hormone sensitive lipase activity), this will increase gluconeogenesis,
Portal/Visceral hypothesis: adipose tissue is in close proximity to the protal vein. Free fatty acids go directly into the portal which goes to the liver. FFA directly blocks insulin action. (inhibiting its receptor)
Endocrine paradigm: the adipose tissue actively secretes hormones d cytokines which lead to insulin resistance
Ectopic fat storage: excess lipid stored in liver.
26
What are the effects of amino acids, glucose and epinephrine on insulin and glucagon secretion
- Glucose promotes insulin secretion
- epinephrine decreases insulin secretion from pancreas
- glucose inhibits glucagon secretion
- epinephrine promotes glucagon secretion from pancreas
*amino acids stimulate both
27
Why do type 1 diabetics have ketoacidosis?
in type 2 you do have insulin working at some low level
Insulin is no longer present which means glucagon is the main hormone.
Glucagon increases hormone sensitive lipase activity which increases free fatty acids in the blood. Free fatty acids will get back to the liver and be converted to acetyl coA (beta oxidation) and then into ketone bodies.
28
Why does diabetes lead to artherosclerosis?
Lipoprotein lipase is activated by insulin. Without insulin you will not break down chylomicrons or VLDL and they accumulate.
29
What is difference between type 1 and type 2
in both there is a GLUCAGON ExCESS
Type 1 diabetes: usually diagnosed at childhood, usually undernourished, a moderate genetic predisposition
- there is a LACK of insulin from destroyed beta cells
- common ketosis
- the acute complication is ketoacidosis
- responsive to insulin
Type 2: diagnosed later in life, usually obese, VERY strong genetic predisposition
- insulin resistance and now the beta cells can't produce enough insulin
- hyperosmolar state
- responsive to hypoglycemic drugs.
30
How does glucagon promote gluconeogenesis in liver?
*doesn't happen in muscle. Glucagon first of all doesn't do anything in muscle and while epinephrine inhibits glycolysis in liver, it promotes glycolysis in the muscle.
When glucose is abundant there is insulin secretion. What we just learned is that insulin promotes PFK2 activity which produces fructose 2,6 bisphopshate. Fructose 2,6 bisphosphate promotes PFK-1 and glycolysis will inhibits Fructose 1,6 bisphosphatase, a component of gluconeogenesis.
Glucagon will inhibit/phosphorylate PFK2 in liver, thereby inactivated PFK1 and activate the phosphatase. Epinephrine also does this.
31
What is the alanine cycle?
| no net production of glucose
It is critical during exercise when insulin is low and protein breakdown is elevated. The whole point is to use glucose as a shuttle for getting rid of the ammonia group that is toxic.
Pyruvate joins with other shit to make alanine. Alanine from the muscle goes the liver, undergoes urea cycle and the carbon backbone is made into pyruvate, then gluconeogenesis to make glucose which goes back into muscle to remake pyruvate for the cycle. This can also be used to generate glucose that goes to RBCs or brain.
32
During long periods of exercise what happens in regards to blood glucose.
What is the preferred energy source of high intensity exercise, low intensity/prolonged exercise
At first glycogenolysis is preferred in like the first 40 min, by 4 hours, glycogenolysis is decreasing as glycogen stores are used up and gluconeogenesis increases.
Your goals of substrate metabolism is to spare muslce glycogen, maintain glucose homeostasi s because depleting glycogen is muy malo.
For high intensity exercise, insulin activity is blocked leading to increase in blood sugar level. Glucose is more metabolically efficient than FA in this case cause it yields more ATP and is fast.
For prolonged exercise you rely more and more on FFA evidenced by the lessening use of glycogen. Because FFA are well stored, it can sustain you longer.
33
How is TAG metabolism during exercise
Fatty acids and TAGs are constantly shuttled. We have something called glyceroneogenesis, a shortened gluconeogenesis that ends at glycerol-3-P
Combined with fatty acids, makes TAGs in both the liver and adipose tissue. TAGs from liver are transported via VLDL into bloodstream and FA are taken up by the adipose tissue via LPL.
Fatty acid from adipose tissue goes to liver for making more TAGs as well as to muscle for FA oxidation.
The byproducts of muscle activity (lactate, pyruvate, amino acids) all can be converted back to pyruvate, undergo glycerogenesis and make G3P, then FA again.
34
I cell disease is a consequence of...what three things
1. single genetic defect
2. absence of a single phosphotransferase from the golgi
3. absence of multiple acid hydrolases from lysosoms.
Proteins destined to be lysosomal acid hydrolases contain phosphorylated mannose residues. A single phosphorylase is mutated and responsible for this tag
35
A patient has respiratory failure due to respiratory distress syndrome. What test on a lung biopsy would be really helpful.
A phosphatidylcholine assay because it is the major phospholipid component of lung surfactant.
36
Patient has hepatosplenomegaly and hypotonia. Patient dies due to progressive liver failure A liver biopsy showed an accumulation of an insoluble and irritating form of glycogen that resembled starch. Which enzyme is likely deficient?
Branching enzyme
Debranching enzyme you will not see accumulation of starch like molecules since gycogen synthase with branching enzyme will correct the structure of glycogen as its activated by insulin. However if the branching enzyme is deficient then the glycogen structure will always be abnormal looking.
37
```
Von Gierkes
Liver Phopshorylase kinase deficiency
Liver branching enzyme deficiency
Muscle phosphofructokinase deficeincy
Liver debranching enzyme deficiency
Which does not belong
```
All of these can result in hypoglycemia and would benefit from oral glucose. Muscle phosphofructokinase deficiency would not because it can't even use glucose.
38
A boy with Type 1 diabetes enters the hospital with comatose and rapid heart rate. What would be happening?
There would be increased glucose uptake, this indicates an overdose of insulin. In addition there will be normal levels of C-peptide since the injection doesn't contain C-peptide, still elevated levels of HbA1c characterisitc of any diabetes, elevated circulating epinephrine and glucagon in response to hypoglycemia.
39
Which 5 symptoms together compose metabolic syndrome?
1. High triglycerides
2. Low HDL
3. Impaired glucose regulation/diabetes
4. Obesity
5. Hypertension
40
What are the primary sources of energy for muscle, liver, brain, RBCs in fasted state
For liver and muscle irregardless fasting or not, its fatty acids
For brain regardless is glucose
For RBCs glucose is also, can't use ketone bodies
41
What medication has the lowest incidence of causing hypoglycemia for a diabetic when given alone
Sufonylurea increase insulin secretion from pancreatic beta cells so no.
Metformin increases muscle sensitivity to insulin. Metformin lowers gluconeogenesis by liver.
42
A patient has hypoglycemia, hyperlactacidaemia, decreased activity of fructose-1,6-diphosphate. What will accumulate
In the gluconeogenesis pathway, alanine, pyruvate, dihydroxyacetone phosphate and fructose 1,6 bisphosphate will accumulate.
43
What does purine nucleoside phosphorylase do?
It results in the release of ribose-1-phosphate.
44
Which three enzymes use thiamine
1. transketolase
2. Pyruvate dehydrogenase
3. alpha ketoglutarate dehydrogenase.
45
What are the consequences of heavy alcohol ingestion on metabolic pathway? explain (5 things)
it all arises from high NADH
3 major, 2 subsequent
1. Lactic acidosis/energy depletion: PDH is inhibited when they sense high energy (NADH), the pyruvate builds up and is shunted to lactate synthesis via lactate dehydrogenase activity.
2. elevated acetyl coA/Fatty acid synthesis is promoted while beta oxidation is inhibited. The acetyl coA builds up, a substrate for FA synthesis and malonyl coA is also made in the process. Malonyl coA inhibits beta oxidation. At the same time, too high energy inhibits glycolysis pathway and rather favors the conversion of DHAP into glycerol 3P. This combined with fatty acids will be made into TAGs, promoting fatty liver.
3. Hypoglycemia: Gluconeogensis is inhibited in addition to glycolysis being inhibited. Actually oxaloacetate gets converted with NADH into fumurate. Going backwards as we know TCA cycle produces NADH. This takes away a substrate from forming PEP for gluconeogenesis. At the same time the lack of ATP from beta oxidation will also prevent gluconeogenesis
4. Ketoacidosis just due to the acetyl coA buildup and not going anywhere. 2 acetyl coA with thiolase makes acetoacetyl coA, HMG lyase takes HMG and makes acetoacetate. With one more NADH will make hydroxybutyrate
5. Secondary to the lactic acidosis is hyperuricemia. There is an antiport in the proximal renal tubule. It trades uric acid for lactic acid out.
46
What are nutrient consequences of alcohol abuse?
1. Kwashiorkor
- low protein in diet
- fatty liver disease
2. mineral deficiencies
Ca: decreased absorption due to fat malabsorption (vitD)
Mg: decreased intake, increased urination, there is vomiting and diarrhea
Zn
Fe
-deficiency: due to Gi bleeding and anemia.
47
Why does alcohol abuse lead to lack of gluconeogenesis?
Because NADPH is a cofactor in the production of fatty acids from acetyl coA.
Fatty acid synthesis is promoted, and malonyl coA will inhibit fatty acid oxidation. Leading to a large reduction in ATP synthesis and gluconeogenesis and glycogen breakdown are energy dependent so both leads to hypoglycemia.
-if gluconeogenesis is inhibited, build up of pyruvate and as a result, lactate.
48
Where is NADPH used?
1. Fatty acid synthesis
2.
49
What is a cofactor in all carboxylases?
Biotin
ex: acetyl coA carboxylase.
ex pyruvate carboxylase
ex. propionyl carboxylase
50
The committed step of fatty acid synthesis, acetyl coA carboxylase. How is it regulated?
Short term
1. Activating: citrate
indirectly
2. Inhibiting: long chain fatty acids, glucagon, epinephrine
Long term
1. Activating: insulin activates citrate lyase which breaks down citrate in to substrate malonyl coA.
2. Inhibiting: glucagon, epinephrine
51
How are blood glucose levels lowered (three processes)
1. Accelerated glycolysis (glucokinase kicks in)
2. Glycogenesis
3. Acetyl coA can be made into fatty acids to make Tags.
52
What is the function of citrate lyase
It uses ATP to break down citrate into oxalaoacetate and acetyl coA. Acetyl coA goes into fatty acid synthesis while oxaloacetate goes on to form malate and then malic enzyme reforms pyruvate.
In the process you make NADPH which makes the citric lyase reaction a significant source of NADPH in lipid synthesizing cells. The pyruvate reenters the matrix is reconverted back into oxaloacetate and then to citrate for the shuttle to continue.
53
How does muscle glycogen store compare to liver glycogen store?
Note that muscle lacks glucose 6 phosphatase so blood glucose is not affected by muscle glycogen stores.
It is only used to generate ATP (stimulated by epinephrine)
54
What enzymes are regulated for glycogen metabolism and how?
phosphorylated phosphorylase is active .
Two enzymes: glycogen synthase and glycogen phosphorylase.
Liver:
Insulin and glucagon
Muscle: insulin and epinephrine
```
Glycogen phosphorylase (liver)
Activating: Glucagon
Inhibiting: glucose 6 phosphate, insulin
-ATP
-Glucose
```
Glycogen synthase (liver)
Activating: glucose 6 phosphate, insulin
Inhibiting: glucagon
Glycogen phosphorylase (muscle)
Activating: Epinephrine, calcium, AMP
Inhibiting: glucose 6 phosphate, ATP, insulin
Glycogen synthase (muscle)
Activating: insulin, glucose 6 phosphate
Inhibiting: epinephrine.
55
What is the pathway for fructose metabolism
Fructose can go down two paths, hexokinase (extrahepatic) or fructokinase, the major one and in the liver
1. Fructokinase, takes fructose and makes fructose 1 phosphate. Fructose 1 phosphate gets converted by aldolase B into glyceraldehyde and DHAP. Glyceraldehyde can be converted to glycerol and then glycerol phosphate which can make TAGS. It can also be made into glyceraldehyde 3 P which can continue down pyruvate. The DHAP can also be made into glyceraldehyde 3 P for glycolysis but also via aldolase A get converted into fructose 1,6 bisphosphate for gluconeogenesis.
* bypasses phosphofructokinase
```
2 Hexokinase (extrahepatic) uses aldolase A!
Hexokinase converts fructose into fructose 6 phosphate and then into fructose 1,6 bisphosphate due to phosphofructokinase activity,
-then aldolase A cleaves it into *glyceraldehyde 3 phosphate and DHAP and undergoes glycolysis or DHAP can go to gluconeogenesis.
```
56
What is the presentation of HFI?
Hypoglycemia and lactic acidosis.
Hypoglycemia is due to blocking of gluconeogenesis and glycogen degradation. BOth is due to sequestering of inorganic phosphate as fructose 1 phosphate but slow aldolase B activity.
Gluconeogensis: requires a lot of energy but also fructose 1 phosphate blocks aldolase B in gluconeogenesis (the reverse reaction)
Glycogen degradation: phosphorylase!
Lactic acidosis: gluconeogenesis is blocked and lactate becomes pyruvate but now accumulates.
57
Descibe galactose metabolism
Starts with galactose and your goal is to make glucose 1 phosphate by using a glucose 1 phosphate?... wtf
Anyways, galactose is converted to galactose 1 phosphate by galactokinase.
-Glucose 1 phosphate is made from glucose 6 phosphate by phosphoglucomutase (an enzyme that works in two directions)
-Then galactose 1 phosphate gets its galactose exchanged with glucose to form glucose 1 phosphate. Phosphoglucomutase strikes again making glucose 6 phosphate and then the phosphatase makes glucse, seems like a fucking worthless pathway.
Aldose reductase like what converts glucose to sorbital also works on galactose and is found in the kidney, retina, lens, nerve tissue, seminal vesicle and ovaries. It converts galactose to galactitol only when galactose is in excess.
58
Describe the hereditary dysfunctions of galactose metabolism
1. Galactokinase deficiency: can't make galactose 1 phosphate, aldolase reductase kicks in and forms galactitol. This accumulates causing cataracts.
There is also galactosemia and galactosuria
2. GALT: is a deficiency in galactose 1 phosphate uridylyltransferase. This time galactose 1 phosphate is also accumulating in the lens, kidneys, liver and nerves. In addition to cataracts, there is liver damage, mental retardation. Galactosemia, galactosuria, jaundice. Also see hyperuricemia due to phosphate entrappment. This increases adenine deaminase activity converting adenine to inosine. Inosine becomes hypoxanthine, then xanthine, then uric acids.
59
What is gluconeogenesis pathway.
You take alanine, lactate or amino acids.
They all get converted into pyruvate. From pyruvate you need to bypass the pyruvate kinase step. Pyruvate carboxylase makes oxaloacetate. That can go into TCA or in gluconeogenesis. Oxaloacetate with PEP carboxykinase is made into PEP. Then PEP gets converted all the way into DHAP and G3P. Via aldolase, the two get converted into fructose 1,6 bisphophate
Then fructose 1,6 bisphosphatase removes a phosphate and makes fructose 6 phosphate. (AMP and fructose 2,6 bisphosphate both inhibit this enzyme. AMP cause low energy, and at this step if there is 2,6 bisphophate there is also insulin action which means glycolysis is promoted.
Then converted into glucose 6 phosphate. Glucose 6 phosphatase found bound to ER removes the phosphate and makes glucose.
*glycerol backbone of TAGs are also used. Glycerol is acted on by glycerol kinase making glycerol 3 phosphate, then via glycerol 3 phosphate dehydrogenase, the glycerol 3 phosphate is converted to DHAP and can undergo gluconeogenesis.
60
Why does fasting lead to liver gluconeogenesis?
When there is fasting there is a lowered glyoclysis for ATP synthesis. What is relied on?
Beta oxidation. Beta oxidation makes a lot of acetyl coA. Acetyl coA inhibits pyruvate kinase which promotes the opposite reaction of pyruvate carboxylase/PEP carboxykinase.
Higher acetyl coA also leads to higher citrate which inhibits PFK1.
61
What are clinical issues of gluconeogenesis of neonates and alcohol.
1. In newborn, premature and fullterm, PEP carboxykinase is present in very low levels. Theyre glycogenesis enzymes have low activity and so their glycogen stores run out quickly. Normally gluconeogenesis would take over but due to the PEP carboxykinase deficiency, they risk hypoglycemia.
2. High NADH in consumption of alcohol pushes two reactions. Oxaloacetate to malate (cause we are making NADH the other way) and also pushes pyruvate to form lactate. This can also lead to hypoglycemia.
62
What is NADPH used for?
1. Fatty acid synthesis: production of palmitate requires 14 molecules of NAPDH..wtf??
2. Cholesterol synthesis - formation of HMG-CoA to melvalonate
3. Nucleotide synthesis, 2 steps
- used by ribonucleotide reductase which takes the diphosphate UDP. Uses NADPH with the ribonucleotide reductase to form deoxyUTP.
- uses NADPH in the conversion of dUMP > dUTP via thymidylate synthase and NADPH + N5, N10 methlene THF.
4. Steroid synthesis - aldosterone, cortisol, cholesterol, and xenobiotic functions where it hydroxylates a substrate to improve solubility. So it can be get rid of. In liver important for bile acid synthesis and calcitriol.
63
What is an essential cofactor used by all amino transferases
Vit B6
CPT-1 uses N-acetylglutamate
High glutamate stimulates arginase to make N-acetylglutamate
High arginine (not to be confused with asparagine which is made from asparatate, the nitrogen donor in urea cycle) sensed by the arginase increases N-acetyl synthetase activity.
64
which amino acids are only ketogenic
Lysine and leucine. Only even carbon skeletons can be used for ketogenesis (acetyl coA). While many are also glucogenic, these cannot produce any of the intermediates and are only ketogenic. Also remember PVT Tim HALL and that these are also essential.
65
IN what 3 pathways do we see glycerol 3 phosphate dehydrogenase being used?
1. Glycerol 3 phosphate dehydrogenase converts DHAP to glycerol 3 phosphate. Glycerol 3 phosphate can be used in TAG synthesis. Don't get it twisted, glycerol kinase takes glycerol and makes glycerol 3 phosphate only in the liver.
2. Gluconeogenesis/Glycolysis: it starts with free glycerol released by TAGs from the hormone sensitive lipase. The glycerol via glycerol kinase is phosphorylated to G3p and then via g3p dehydrogenase makes DHAP which is an intermediate in glycolysis.
3. Glycerolphosphate shuttle: NADH is used to make glycerol 3 phosphate. G3P Dh once again make DHAP at the same time generated FADH2, 1 ATP lost with this shuttle.
66
What diabetes drug delays the absorption of dietary carbohydrates?
Acarbose.
67
What is disulfiram?
| abali aunt
It inhibits acetaldehyde dehydrogenase which leads to accumulation of acetaldehyde and therefore feel like shit. Begin 10 min after consumption of any alcohol and last for 1 hour.
68
What is MEOS microsomal ethanol oxidizing system and how alcohol abuse can affect it.
When there is excess alcohol that it overcomes the normal metabolic route, it enters the MEOS pathway. The MEOs pathway uses CYP2E1 to metabolize alcohol to acetaldehyde.
It however metabolizes alcohol in addition to
- acetaminophen
- isoniazid
- phenobarbital
So normally this CYP will metabolize drug for secretion
- alcohol with drug intake will compete with the CYP causing the drug to not be metabolized and also less excretion (however don't think of this wrong way, if drug isn't metabolized that doesn't do anything.
- even if a chronic heavy drinker drinks, will be the same result. No drug effectiveness
* now for chronic heavy drinkers that are sober, when they take drugs. THeir CYP activitty is so fucking ramped up from all the alcohol that they metabolize super fast, you get drug toxicity. Lots of excretion.
69
When someone is exercising stress hormones are ramped up, (epinephrine, glucagon). However glycolysis in inhibited in the liver and other places except the muscle. WIthout glycolysis no G3p is made to resynthesize TAGs for transport and especially fatty acids to the muscle. What is done in this situation.
So Tags come from liver in VLDL, to adipose tissue. LPL is activated, taking up fatty acids.
In the adipose tissue the fatty acids are resynthesized into tags, and then hormone sensitive lipase releases fatty acids bound to albumin to the muscle.
Now you need G3p to synthesize those TAGs to mobilize the fatty acids for hormone sensitive lipase to work?...
That is why glycerogenesis takes care of this. It takes pyruvate and goes the gluconeogenesis pathway. Until it gets the DHAP where it then is converted by glycerol 3 phosphate dehydrogenase to make G3p/
70
what is sovaldi?
Hep C cure drug that has a protected phosphate group.
Intracellular metabolism converts this drug into an active analog of uridine triphosphate which is incorporated and acts like a chain terminator.
71
Why does ADA deficiency lead to exercise intolerance.
During exercise you need more TCA intermediates. So when AMP is made into IMP during degradation. That IMP can be resynthesized to AMP and during that process, fumarate is released.
That fumurate can enter the TCA cycle and be used to generate ATP.
72
What enzymes have feed forward mechanisms.
PRPP has a feed forward regulation in purine synthesis. It activates PRPP amido transferase to make PRA using glutamine (Azaserine and DON are inhibitors of thiss process)
Fructose 1,6 bisphosphate has a feed foward effect on pyruvate kinase.
73
A child has hypoglycemia, low levels of carnitine and acyl carnitine in blood. FFA in blood are elevated.
Deficiency in what?
Carnitine transporter (kidney).
Low carnitine means there is less fatty acid oxidation and ketogenesis.
There is low carnitine in blood because it is just exported in urine.
CPT1 deficiency would increase blood carnitine by inhibiting carnitine transporters in the kidney via acylcarnitines. It also decreases uptake of carnitine out of circulation.
74
What are the consequences of MCAD?
1. dicarboxylic acidosis - fatty acid with additional carboxyl group added in plasma and urine (medium chain dicarboxylic acids)
2. Hypoketotic hypoglycemia (can't use acetyl coA from beta oxidation for ketogenesis, can't use gluconeogenesis (no ATP)
3. Treatment: avoid fasting, frequently feed and supplement of carnitine
75
A patient has elevated hydroxybutyryl carnitine concentration
Hydorxybutyryl is a short chain fatty acid.
It there is elevated carnitine then there must be something wrong with its handling in the mitochondria.
Short chain hydroxyacyl CoA dehydrogenase.
hypoketotic hypoglycemia (no acetyl CoA and not enough ATP)
76
Why would hyperammonemia and lactic acidosis occur in someone who can't undergo beta oxidation?
Hyperammonemia: there is increased muscle breakdown for the gluconeogenesis however that cannot occur, so the proteins get degraded and build up of ammonia
Lactic acidosis because gluconeogenesis promotes lactic acid usage.
77
What are acylglycine tests?
acyl CoA + glycine = N-acylglycine.
With accumulation of acylCoA this will happen.
For an MCAD deficiency, there would be enriched C6,C8, C10 of both acylglycines and acylcarnitines
78
What hints at a glut2 transporter deficiency?
Why give citrate in addition to thiamine and dichloroacetate to PDH deficiency?
Low fasting blood glucose levels because it is found in the liver and gluconeogenesis produces glucose that goes out of GLut2.
Citrate just to bypass the PDH step and make some good ol ATP.
79
What enzyme of pyrmidine synthesis is inhibited by
5-FU
Methotrexate
Hydroxyurea
What is the primary endproduct of pyrmidine synthesis?
5-FU: thymidilate synthase
Methotrexate: DHFR
Hydroxyurea: ribonucleotide reductase
80
What are the inhibitors of PRPP synthetase
What is the committed step of the purine pathway?
Purine di or trinucleotides inhibit PRPP synthetase
PRPP amidotransferase is the committed step, the synthesis of phosphoribosylamine from PRPP.
81
What is the mechanism of action of folic acid analogs?
They inhibit DHFR and thus purine and TMP synthesis is inhibited. This leads to halt in DNA synthesis and cell death.
82
What are the possible causes of gout?
1. Lesch-Nyhan
2. PRPP excess
3. Decreased excretion of uric acid
4. G6PDH deficiency
83
What are differences between CPS1 and CPSII?
CPS1 depends on N-acetylglutamate as an allosteric activator. CPS1 functions in the urea cycle
CPS1 is found in the mitochondria
CPS1 takes free ammonia (released by glutamate dehydrogenase)
CPS2 is in the cytoplasm, it is the committed step of pyrmidine synthesis, it uses glutamine as a source of nitrogen.
84
What inhibits ribonucleotide reductase?
What causes orotic aciduria? What accumulates and what would alleviate symptoms?
dATP + hydroxyurea
Enzyme deficiency is UMP synthase.
1. Orotate phosphoribosyl transferase to form OMP
2. OMP decarboxylase to form UMP
The accumulating molecule is orotate
And you give uridine and cystidine to alleviate symptoms
85
A women has an MCV of 120 and normal methymalonic disease. Homocysteine is also elevated
What is the deficiency?
What is the deficiency?
Folic acid: you have macrocytic anemia (MCV should be >100.)
But normal methylmalonic acid which is only elevated in B12 deficiency
86
What are two other sources of electrons for coQ?
1. fatty acyl oxidation via fatty acyl- coA dehydrogenases
2. Glycerol 3 phosphate dehydrogenase of the glycerol phosphate shuttle.
Both generate FADH2.
87
How does HMP pathway relate to fatty acids?
Fatty acid synthesis requires molecules of NADPH.
beta oxidation releases NADH. This is what is meant b NADPH being used for synthetic reactions.
88
What four factors influence whether glucose undergoes aerobic or anaerobic glycolysis?
1. the quantity of mitochondria
2. availability of oxygen
3. The NAD+/NADH ratio
4. The quantity of active PDH.
89
The committed step of TCA, isocitrate to alpha-ketoglutarate, what is that regulated by?
NADH, ATP, ADP and calcium.
Actually none of the TCA cycle is regulated by insulin/glucagon
PDH, PK, PFK2 (NOT1) and GK expression! (fructose6/1P otherwise)
90
Are phospholipids and glycolipds easily absorbed
Are medium and short chains FApackaged into chylomicrons?
No and NO
Phospholipids and glycolipids both have polar heads.
Medium and short chain FA are easily absorbed and enter the portal vein directly.
91
Does the HMP pathway use ATP?
It does not use ATP because technically the pathway begins with Glucose 6 phosphate which would have used a ATP to generate.
92
Why do unsaturated FA yield less energy?
The double bond needs to be isomerized to align with beta oxidation activity. Part of that involves adding a water to the double bond. The unsaturated FA yields less energy because it is less reduced than saturated.
93
If someone's excretion of creatinine is much lower than normal, what could cause that?
Kidney failure: dietary creatine is not relevant since we make it from our amino acids. In muscle creatine is converted to creatine phosphate which is NONenzymatically cyclized to creatinine. Kidneys are responsible for excretion of creatinine and kidney failure would have elevated creatinine in blood.
94
What does a sudden rise in muscle Ca2+ concentration do?
It will lead to a signal cascade which activates phosphorylase kinase ewhich in turn activates glycogen phosphorylase.
95
Classical galactosemia is deficiency of what
GALT (galactose 1 phosphate uridyltransferase)
96
Describe the polyol pathway
Glucose is reduced to sorbital by aldose reductase. NADPH is used.
Then sorbital is Oxidized to fructose with sorbital dehydrogenase using NAD+ to make NADH.
97
How does insulin affect G6PDH
There is no phosphorylation event. Insulin will increase synthesis of G6PDH.
98
What would G6PDH deficiency do to fatty acid metabolism?
Lead to accumulation of lipid oxidation products due to inhibited synthesis.
99
Why are RBcs so devastated by fked up HMP?
The HMP pathway is their sole means of making NADPH.
They lack mitochondria so they can't make NAPDH via malic enzyme or nicotinamide nucleotide transhydrogenase.
100
How are the effects of epinephrine different in the heart vs the liver
In the liver, phosphorylation inhibits PFK2 activity. IN the muscle, PFK2 activity is promoted because you want accelerated glycolysis.
101
Which enzyme of glycogen synthesis is regualted by phosphorylation of the enzyme
Glycogen synthase
102
What happens to acetyl coA in the early hours of a fast vs later (several days)
acetyl coA > TCA in the early hours of a fast
acetyl coA > ketogenesis later.
103
About GAGs what are their structures, how are they linked, do all contain sulfate groups? what is charge
Linear and unbranched
They are O linked proteoglycans
Hyaluronic acid does not contain sulfate
GAGs are negatively charged.
104
How do Purines regulate pyrimidine synthesis?
Via ATP. The precursors to pyrmidine synthesis are 2 ATP, CO2 and glutamine.
105
How is PFK2 different in muscle
Muscle PFK2 can't be directly phosphorylated like it can in liver.
It comes down to levels of fructose 6 phosphate.
Epinephrine leads to breakdown in muscle and increased fructose 6 phosphate for PFK-1 to use in glycolysis, which is how it accelerates glycolysis in muscle, inhibits it in liver by getting PFK2 phosphorylated.
106
Exercising increases muscle breakdown, how does all the urea get excreted?
Glucose alanine cycle.
Pyruvate makes alanine through ALT. The alanine goes from muscle to liver, the ammonia gets excreted and pyruvate gets turned into glucose. Then back to muscle
107
What is AMP deaminase?
Not to be confused with Adenine Deaminase, this enzyme converts AMP to IMP.
Then IMP can be joined with aspartate to make adenylsuccinate and back to AMP.
This genereates a fumurate that can be used in TCA.
This is known as the purine nucleotide cycle and may lead to exercise intolerance if defective.
