What path takes you from Phenylalanine to Epinephrine?
Phenlyalanine--> (Phenlyalanine hydrylase)--> Tryosine--> (tyrosine hydroxylase)--> DOPA--> (DOPA decarboxylase)--> Dopamine--> (Vit C)--> Norepinenphrine--> (SAM)--> Epinephrine
How do we get melanin production?
What wold cause albinism?
DOPA--> Melanin via Tyrosinase
INhibition of tyrosinase leads to albinism
Musty odor, ID, fair skin, exzema; obviously PKU. What's the EnZ responsible?
What will increase in the body?
What AA becomes essential?
Due to Decreased phenylalanine hydroxylase or Decresaed tetrahydrobiopterin cofactor (malignant PKU). Tyrosine becomes essential. INCREASED phenylalanine -->excess phenylketones in urine.
Mom has low phenylaline hydroxylase and doesn't monitor her diet during her pregnancy. What will happen to the baby as a result?
Mom has PKU:
Mom drinks lots of diet soda and shit with artificial sweatners
Findings in infant: microcephaly, intellectual disability, growth retardation, congenital heart defects
Mom is changing her babies diaper and notices it smells like burnt sugar. The doctor discusses nutritional changes to be made in the infants diet to deal with this including Isoluecine, Leucine and Valine. What's the dx and enZ deficiency?
What are consequences if not given a strict diet?
What needs to be supplemented in the diet?
Maple Syrup Urine Diseaes: Blocked degradation of branched amino acids (Isoleucine, Leucine, Valine) due to DECREASED α-ketoacid dehydrogenase (B1).
Causes α-ketoacids in the blood, especially those of leucine.
Causes severe CNS defects, intellectual disability, and death.
Treatment: restriction of isoleucine, leucine, valine in diet, and thiamine supplementation.
You are doing in-patient rotations at the hospital and notice a nurse talking a urine sample from your pt who is there for horrible joint pain. The urine is BLACK and she's explains she would expect it to be because it was sitting out for awhile, she was running behind.
What disease does this pt have?
What associated findings would possibly be present?
Congenital deficiency of homogentisate oxidase in the degradative pathway of tyrosine to fumarate--> pigment-forming homogentisic acid accumulates in tissue
Autosomal Recessive and often benign
dark connective tissue, brown pigmented sclerae, urine turns black on prolonged exposure to air. May have debilitating arthralgias (homogentisic acid toxic to cartilage).
You are rotating through optholmogy even though eyeballs are disgusting and a young tall man is brought in to clinic with his mother. He is very tall and intellectually disabled. He has been having vision issues and it is found he has a lens subluxation (downward and inward)
What pathway is disrupted in this patient?
What AA aren't reabsorbed in this pt?
HIGH homocysteine in urine, intellectual disability, osteoporosis, marfanoid habitus, kyphosis, lens subluxation (downward and inward), thrombosis, and atherosclerosis (stroke and MI)
Pt recently passes a kidney stone and the lab tells you its a cystein stone
What is the defect in your pts Kidney?
What AA are lost in the urine?
How do you tx your patient?
Hereditary defect of renal PCT and intestinal amino acid transporter that prevents reabsorption of Cysteine, Ornithine, Lysine, and Arginine (COLA).
Excess cystine in the urine can lead to recurrent precipitation of hexagonal cystine stones
Treatment: urinary alkalinization (e.g., potassium citrate, acetazolamide) and chelating agents (e.g., penicillamine) solubility of cystine stones; good hydration
Review the graph to get a feel for Glycogen regulation by insulin and glucagon
Glycogen: Branches have α-(1,6) bonds; linkages have α-(1,4) bonds.
How is glycogen processed differently in the skeletal muscle vs hepatocytes
Muslces: Glycogen undergoes glycogenolysis--> glucose-1-phosphate---> glucose-6-phosphate, which is rapidly metabolized during exercise.
Glycogen is stored and undergoes glycogenolysis to maintain blood sugar at appropriate levels. Glycogen phosphorylase liberates glucose-1-phosphate residues off branched glycogen until 4 glucose units remain on a branch. Then 4-α-d-glucanotransferase (debranching enzyme ) moves 3 molecules of glucose-1-phosphate from the branch to the linkage. Then α-1,6-glucosidase (debranching enzyme ) cleaves off the last residue, liberating glucose.
You pt had a recent episode of severe fasting hypoglycemia but has tested negative for diabetes. Labs show Increased Blood lactate, increased uric acid and high TGs. On physical exam you can palpate her liver.
Von Gierke Disease
Little boy comes in with heart fail and ties. Labs show he died from an enZ deficiency. This disease is autosomal recessive.
Pompe disease: Lysosomal α-1,4-glucosidase (acid maltase) deficiency
Pompe trashes the Pump (and liver and muscle)
A mother brings her daughter into the office. The 10 yo recently joined a competitve soccer team and after the game had an episode of painless hematuria but her legs were very sore. What enZ deficiency could be responsible for pts condition?
Skeletal muscle glycogen phosphorylase (myophosphorylase) deficiency:
Increase glycogen in muscle, but muscle cannot break it down--> painful muscle cramps, myoglobinuria (red urine) with strenuous exercise, and arrhythmia from electrolyte abnormalities
Tx: B6 supplement
What mild form of glycogen disorder causes hypoglycemia,hyper TG but no change in blood lactate levels?
debranching enZ defient
Pt comes in with longstanding peripheral neuropathy (does not have diabetes) and recently has been having kidney issues. What EnZ deficiency could be causing his problems? What product would build up as a result?
Peripheral neuropathy of hands/feet, angiokeratomas, cardiovascular/renal disease.
Deficient: α-galactosidase A
Build up: Ceramide trihexoside
(Ceira is a Fabulous Gal)
You are in the pathology lab and your attending points out a cell full of lipid laden macrophages that looks like wipspy paper. The note on the pt says that he has pancytopenia and is in the hospital for a femur fracture. What is the pts disease?
Gaucher cells = crumpled tissue paper
Deficient: Glucocerebrosidase (β-glucosidase)
Build up: Glucocerebroside
Also see: Hepatosplenomegaly, pancytopenia,osteoporosis, aseptic necrosis of femur, bone crises, treatment is recombinant glucocerebrosidase.
60 yo pt comes in with his wife, he has progressive dementia and hepatosplenomegaly. During the PE you notice a red spot in the macula with the fundascope.
What's the Dx?
(Progressive neurodegeneration, hepatosplenomegaly, foam cells (lipid-laden macrophages) “cherry-red” spot on macula )
*presents sim to Tay-Sachs; but Neimann Pick is longer name thus has larger organs!
Pt comes in with husband. She has cherry red spot on macula and has progressive dementia and normal AST/ALT. What do you Dx her with?
(simular to Niemann pick but NO hepatosplenomegaly)
4yo child comes in with mother... he points to his fingers and says they feel funny. The mother mentions concerns about that but also is concerned that he is smaller for his age and doesn't seem to interact as well with other kids. You think it may be because he has really dorky glasses but don't say anthing bc that would be rude.
Based on the pathology attached, what enZ is this pt most likely deficient in? What product build up is there?
Deficient in Galactocerebrosidase
Build up of Galactocerebroside or psychosine
Peripheral neuropathy, developmental delay, optic atrophy, globoid cells
Young pt comes to the clinic with ataxic gait and dementia. The disesease she has causes central and peripheral demyleniation. What enZ deficiency is this and what build up product is there?
Arylsulfatase A defeiciency
Cerebroside sulfate build up
You are rounding in peds and a women brings her son in for a well-child. The baby is hideous, more then babies usually and has labored breathing. You can palpate the spleen and liver and notice corneal clouding. What is the EnZ defeiciency?
What is the buildup?
Hurler Syndrome: Mucopolysacchoridoses
Build up of: Heparan sulfate, dermatan sulfate
These children have developmental delay, gargoylism, airway obstruction, corneal clouding, hepatosplenomegaly.
You are at the grocery store and this little kid that looks like a gargoyle comes and kicks you in the leg for no reason then he punches his mom in the face. You think he for sure has an enZ deficiency, what is it?
What is the build up?
Hunter syndrome: (milder form of Hurler)
Deficient in: Iduronate sulfatase
Build up in: Heparan sulfate, dermatan sulfate
(Hunters see clearly (no corneal clouding) and aggressively aim for the X (X-linked recessive).
Long chain FA degradation requires ________ transport into the mitochondiral matrix.
IF this is deficiency we end up with toxic accumulation causing weakness, HYPOtonia, HYPOKETOTIC HYPOglycemia
What results when we have decreased Acyl-CoA dehydrogenase
Increased Dicarboxyclic acids, DECREASED glucose and ketones
Acetly-CoA is a +allosteric regulator of pyruvate caboyxylase in gluconeogenesis thus LOW actely-CoA = LOW fasting glucose
How do the following situations cause increased ketones (fruity breath)
1. high FA and AA breakdown
3. Strarvation and DKA
FA and AA are metabolized in liver to acetoacetate and B-hydroxybutyrate for use in msl and brain
Alcoholics you get excess NADH which shunts oxa to malate which builds up Acetly CoA; this shunts glucose and FF toward prouction of ketones
In Starvation and DKA, oxaloacetate is depleated
How is blood glucose levels maintained 1-3 days into starvation?
Blood glucose levels maintained by:
Adipose release of FFA
Muscle and liver shift fuel use from glucose--> FFA
Hepatic gluconeogenesis from peripheral tissue lactate and alanine, and from adipoase tissue glycerol and propionyl CoA
Cholesterol needed to maintain cell membrane integrity and to synthesize bile acid, steroids, and vitamin D.
Rate-limiting step catalyzed by _______ (induced by insulin)
HMG-CoA reductase ( converts HMG-CoA --> mevalonate)
2⁄3 of plasma cholesterol esterified by ________
_____causes degradation of TGs circulating in chylomicrons and VLDLs. Found on vascular endothelial surface.
________responsible for degradation of TGs remaining in IDL
________mediates transfer of cholesterol esters to other lipoprotein particles.
lecithin-cholesterol acyltransferase (LCAT).
Lipoprotein lipase (LPL)
Hepatic TG lipase (HL)
Cholesterol ester transfer protein (CETP)
Liver and intestine make nascent HLD which then becomes mature HDL via ______
How are Choelsterol esters transfered to other lipoprotein particles from the HDL?
Nascent--> (LCAT)--> Mature HDL
Mature HDL --> Cholesterol ester transfer protein =CETP--> offload esters
Apolipoprotein key in mediating remnant uptake.
Found in chylomicron, remnants,s VLDL, IDL and HDL
What Apo is in charge of activating LCAT
Found in HDL and Chylomicrons
What is the role of Apo-CII?
Key lipoprotein lipase cofactor
What is the role of Apo B-48?
What about Apo-B-100?
48: mediates chylomicron secreation
100 binds LDL receptor
Delivers dietary TGs to peripheral tissue. Delivers cholesterol to liver in the form of chylomicron remnants, which are mostly depleted of their TGs. Secreted by intestinal epithelial cells.
1. Delivers hepatic TGs to peripheral tissue. Secreted by liver.
2. Formed in the degradation of VLDL. Delivers TGs and cholesterol to liver.
3. Delivers hepatic cholesterol to peripheral tissues. Formed by hepatic lipase modification of IDL in the peripheral tissue. Taken up by target cells via receptor-mediated endocytosis.
4. Mediates reverse cholesterol transport from periphery to liver. Acts as a repository for apolipoproteins C and E (which are needed for chylomicron and VLDL metabolism). Secreted from both liver and intestine. Alcohol Increases synthesis.
Patient has increased levels of cholesterol and TGs in blood as well as chylomicrons but not at increased risk for atherosclerosis.
Type I Hyper-Chylomicronemia
Causes: auto-Recessive with Lipoprotein Lipase deficiency or altered apolipoprotein C-II
Causes: pancreatitis, hepatosplenomegaly and eruptive/pruitic xanthomas
Patient has SUPER high LDLs and elevated Total cholesterol. TG are nomal.
DX and risks?
IIa Familial Hyper-Cholesterolemia
Autosomal dominant. Absent or defective LDL receptors. Heterozygotes (1:500) have cholesterol ≈ 300 mg/dL; homozygotes (very rare) have cholesterol ≈ 700+ mg/dL. Causes accelerated atherosclerosis (may have MI before age 20), tendon (Achilles) xanthomas, and corneal arcus
Patient produces shit ton of VLDL and has elevated TG. Whats the Dx and associated risk?
Type IV Hyper-Triglyceridemia
Autosomal dominant. Hepatic overproduction of VLDL.
Hypertriglyceridemia (> 1000 mg/ dL) can cause acute pancreatitis.
What is the biologically active form of pantothenic acid?
What reactions does it play and essential role in?
Panthetoic = Coenzyme A; key for acetlylation reacttions
In TCA: binds oxaloacetate to form Citrate and then succinly CoA
Key in synthesis of Vitamins A, D, and chosterole, steroids, heme A, Fatty Acids, AA and protein
Huntington disease is an AD diseaes and we see CAG repeats in gene that codes for huntingtin. What is the mechanism by which the mutated huntingtin causes disease?
See transcriptional repression (silencing) and see regulation of transcription occuring in part dt histones that affect accessiblity of genome for transcription. Acetlyation of histones weakens DNA-histone bond and makes DNA MORE accessible for transcription factors