Misc Flashcards
What are Gags and what are the 6 GAGs
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
What is I cell disease?
similar to Pseudo-hurler polydystrophy
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.
Which GAG degradation issues result in accumulation of:
Dermatan sulfate
Heparan sulfate
Keratan sulfate
Chondroitin sulfate
Dermatan sulfate: Hunter, Hurler, Sly
Heparan sulfate: Hunter, Hurler, Sly, Sanfillipo.
Keratan sulfate
What are azaserine
What is 6-Diazo-5-oxonorleucine (DON)
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.
What are methotrexate and aminopterin and 5 flurouracil
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.
What is Bactrim?
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.
What is ribovarin and mycophelonic acid
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.
What happens in Lesch-Nyhan syndrome?
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
What is going on in SCID (severe combined immunodeficiency)
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!
What results from PNP deficiency (purine nucleoside phosphorylase)
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.
What is allopurinol?
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.
What happens in orotic aciduria?
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.
How does acyclovir work?
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
What are the three important amino acid/keto acid pairs?
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.
What is tetrahydrobiopterin?
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.
What three things are cofactors in the conversion of Norepinephrine to epinephrine?
- S-adenosyl methionine
- Methycobalamine - B12
- Folate
Ultimately it is a transfer of a methyl group.
What is creatine?
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.
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
This is a description of Nieman Pick Disease. The answer is D. sphingomyelin.
What metabolic things are only in liver and muscle
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
What is phenytoin?
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;.
What is leucovorin (aka folinic acid)
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.
What is the SAM synthesis reaction
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.
What does B12, have in common with amino acid degradation and odd cahin fatty acid degradation
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.
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?
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
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.
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
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.
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.
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.
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.
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.
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.
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.
I cell disease is a consequence of…what three things
- single genetic defect
- absence of a single phosphotransferase from the golgi
- 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
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.
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.
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.
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.
Which 5 symptoms together compose metabolic syndrome?
- High triglycerides
- Low HDL
- Impaired glucose regulation/diabetes
- Obesity
- Hypertension
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
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.
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.
