Biochemistry and Genetics Flashcards
Trinucleotide Repeat disorders with mnemonic
Try(nucleotide) Hunting for my Fragile (x) cage Free(iedrich’s) eggs
Huntingon’s
Fragile X
Friedrich’s Ataxia
Defect in Fragile X
CGG trinucleotide repeat in in FMR1 gene causes hypermethylation and thus reduced expression -> delayed neural development
What is the enzyme defect in porphyria cutanea tarda (PCT)?
Uroporphyrinogen Decarboxylase (UROD)
What vitamin deficiency is present in Pellagra? Who gets pellagra?
Vitamin B3 - niacin
Often seen in malnourished populations–either GI malabsorption and/or alcoholics
What is vitamin B3/niacin needed for?
Cofactor for isocitrate DH, alpha KG DH, and malate DH
Niacin is a component of NAD, often used for catabolic reactions
If you see glycine in the vignette, you should think…
Collagen
Glycine is really small and therefore every 3rd AA in collagen is glycine so the 3 strands can wind around each other
Gly-X-Y-Gly- …etc
If you see alanine in the vignette, you should think…
Patient is starved so muscle cells are breaking down for food
Alanine goes to the liver where the amino group is pulled off (makes urea) and then the remaining 3 carbon backbone is PYRUVATE! Which can then be used for gluconeogenesis
If you see valine, leucine, or isoleucine in a vignette, you should think…
Maple Syrup Urine Disease (MSUD)
If you see proline in the vignette, you should think…
Proline hydroxylase enzyme
Collagen
Vitamin C needed for Co-translation
Genetic disorder: Ehlers-Danlos
Nutritional: Scurvy
If you see phenylalanine in the vignette, you should think…
PKU
Phenylalanine hydroxylase is deficient
Mental retardation, “musky” smelling diapers…
PKU
Phenylalanine hydroxylase needs what to work?
Tetrahydrobiopterin THB)
Phenylalanine and tyrosine are precursors to what biologically active molecules?
Catecholamines
Melanin
T3,T4
What is the treatment for CML?
Imatinib (Gleevec), a tyrosine kinase inhibitor
What is tryptophan a precursor for?
Serotonin
Niacin
Mnemonic for presentation of Pellagra…
3 D’s:
Dermatitis (red scaly rash)
Diarrhea
Dementia
What AA is used to aid acid excretion in the setting of metabolic acidosis?
Glutamine
Glutamine drops the amino groups which then combine with H+ to be excreted in the urine as NH4+
When the H+ is given up from H2CO3, the HCO3- then goes back into the blood to bring up pH
Vitamin C is a co-factor for _____ and _____ hydroxylase needed for _______ formation.
Proline
Lysine
Collagen
_____ is a precursor AA for NO and Urea
Arginine
What are the positively charged AAs? What are they used for?
Lysine
Arginine
Histidine
^used for histones (esp Lys and Arg)
What sequence is at the 3’ end of tRNAs?
CCA
Which AA is used to make urea?
Aspartate
Which AA is used to make GABA?
Glutamate
Methionine is needed for ___________ (enzyme)
S-adenyl-methionine
When the methyl is given up it becomes homocystine!
^Homocystine is a dangerous thing to have in excess because it has a free sulfhydryl
_______ (AA) is used for N-glycosylation in the ER
Asparagine
What are the essential AAs? (mnemonic)
PVT TIM HALL (Arrrggg PHuck you)
Phenylalanine
Valine
Tryptophan
Threonine
Isoleucine
Methionine
Histidine
Arginine
Leucine
Lysine
(Arginine is essential only during periods of positive nitrogen balance because normally arginine can be made by the urea cycle)
In PKU adults, what AA becomes essential i.e. what needs to be supplemented?
Tyrosine. They have to have very low phenylalanine and Phe is the precursor for tyrosine
In competitive inhibition Km _____ and Vmax ______
Km: Changes
Vmax: Does not change
In noncompetitive inhibition Km _______ and Vmax __________
Km: Does not change
Vmax: Changes
Where do you find Glut 4 transporters?
Fat (adipose) and muscle
What glucose transporter do you find in the liver? Where else is it found?
Glut 2.
Very responsive to changes in blood glucose (enzymes live just below the Km normally -> first order kinetics). More glucose in the blood = more glucose delivery in the liver
Note: Glut 2 is also found in BETA CELLS, and kidneys
What glucose transporters do you find in the brain, RBCs, and most tissues in the body?
Glut 1 and 3
No matter how hyper or hypoglycemic you are, these transporters are always at Vmax (zero order kinetics) to preserve glucose delivery to the brain
Parietal cells stain ______.
Pink
Protruding tongue, upward slanted palpebral fissures, excessive skin at the nape of the neck = ?
Downs
Other than nondisjunction, what is the second mechanism of Down Syndrome?
Robertsonian translocation t(14;21)
Accounts for ~5% of cases
What is classic galactosemia? What is the inheritance?
Autosomal recessive
COMPLETE absence of galactose-1-phosphate uridyl transferase.
Newborns present within DAYS with jaundice, vomiting, and hepatomegaly, sunken fontanelle, cataracts, hemolytic anemia, E.coli sepsis
What is the inheritance of Hemophilia B? What factor does it affect?
X-linked recessive
Factor IX
What is the inheritance of Leber hereditary optic neuropathy? How does it present clinically?
Mitochondrial
Progressive bilateral optic neuropathy leading to complete blindness.
What is the inheritance pattern of Rett syndrome? How does it present clinically?
X-linked dominant
Progressive neurodegeneration and stereotypical hand movements.
How does Lesch Nyhan present clinically?
Self-mutilation, hyperuricemia, dystonia, choreoathetosis within the first few years of life.
Note, it is X-linked recessive so almost always will present in boys.
What enzyme is deficient in Lesch-Nyhan syndrome? What is its function?
HGPRT, an enzyme that normally functions in the purine salvage pathway. When not functioning, guanine and hypoxanthine get degraded into uric acid instead of being salvaged.
As a result PRPP synthetase and other enzymes of the de novo purine synthesis pathways will be upregulated.
Deficiency in Aldolase B = ??
Hereditary fructose intolerance (and therefore sucrose intolerance as well)
Leads to hypoglycemia and vomiting after fructose ingestion -> failure to thrive, liver and renal failure.
Often will present as soon as a baby starts eating solid food (no longer just breast milk)
The first 12-18 hours of fasting = ________
then… ______
Glycogenolysis. Once hepatic glycogen stores are depleted, gluconeogenesis begins. e.g. OAA -> PEP
What are the 2 possible fates ond to f cAMP after it is made by G(alpha)s signaling after hormone secretion?
- degradation by phosphodiesterase (PDE)
- Activation of PKA
PDE is constitutively active. When a hormone has bound to its receptor, Gs makes SO much cAMP, that it overwhelms the PDE and thus PKA is activated.
What are the physical features of Fragile X?
Large ears, long face, prominent forehead, prominent chin, macroorchidism
How is Duchenne Muscular Dystrophy inherited? What does it cause?
X-linked recessive
Usually a deletion in dystrophin gene (can be nonsense mutation) that causes either frameshift or truncated protein.
How does Duchenne Muscular Dystrophy present clinically?
Progressive proximal muscle weakness
Calf pseuohypertrophy
Elevated CK
Gowers sign (using hands to push on legs to stand)
How are sphingolipidoses inherited? What is the exception?
Autosomal recessive
Exception: Fabry’s which is X-linked recessive
How does Niemann-Pick present clinically?
MAY see a macular cherry red spot (remember Tay-Sachs is the major cherry red spot disease)
Progressive neurodegeneration
Hepatosplenomegaly
Hypotonia
Death by age 3
The oxidative/irreversible/first half of the pentose phosphate shunt generates ____ and _____. What are each of them used for?
NADPH and Ribulose 5 Phosphate
NADPH used in cholesterol and fatty acid synthesis AND in glutathione antioxidant mechanism
R5P is used for nucleotide synthesis OR entering the glycolytic pathway
What is the most common enzyme deficiency with a defect in fatty acid beta oxidation? What blood tests would indicate this defect?
Hypoketotic hypoglycemia after a period of fasting (i.e. no acetate or ketones)
Most common enzyme deficiency = acyl-CoA DH
How does MSUD present clinically?
Within first few days of life:
Progressive irritability, poor feeding, lethargy, increased muscle tone, sweet smelling urine
What blood level will be elevated in MSUD (pathognomonic) ?
Elevated branched-chain amino acids
What are the 3 nitrates and what are their uses?
Nitroprusside - HTN
Nitroglycerine - angina
Isosorbide dinitrate - angina
___(AA) -> NO -> Soluble guanylate cyclase -> cGMP -> Protein kinase G -> relaxation of smooth muscle/vasodilation
Arginine
How does ANP (atrial natriuretic factor) cause vasodilation?
Binds transmembrane receptor -> cGMP -> Protein Kinase G -> relaxation
Phosphorylated _______ leads to muscle contraction.
Myosin light chain
What steps of the TCA cycle are thiamine-dependent? (and thus suffer in alcoholics who are typically thiamine-deficient)
Pyruvate DH
alpha-KG DH
What is the CAAT box?
A highly conserved promoter region in eukaryotes that usually precedes the TATA box.
Serves as a binding site for RNA Pol II and general transcription factors.
How does pyruvate DH deficiency present?
Acetyl-CoA is generally produced from pyruvate to enter the TCA cycle. Absence of pyruvate DH leads to a build up of pyruvate that gets shunted to lactate via lactate DH -> this causes life threatening lactic acidosis.
What are the 2 “ketogenic” (i.e. cannot be made into pyruvate) AAs?
Lysine and leucine
They are made directly into acetyl-CoA not pyruvate, so are helpful in pyruvate DH patients
What do Glut 4 receptors do in response to insulin?
Glut 4 receptors move to transmembrane positions in adipose and muscle
Glucagon -> Protein ______ -> glycogen ______ -> …
Glucagon -> protein kinase -> glycogen phosphorylase -> glycogenolysis
Insulin -> Protein ______ -> glycogen ______ -> …
Insulin -> protein phosphatase -> glycogen synthase -> glycogen synthesis
What G protein does the pertussis toxin cause a defect in? via what?
Gialpha via ADP-ribosylation that inhibits it (i.e. inhibiting the inhibitor) ultimately causing increased cAMP
Both cholera toxin and E.coli toxin cause ADP-ribosylation of G___ leading to ______ cAMP.
Gsalpha (i.e. STIMULATORY G protein) leading to increased cyclic AMP.
Diphtheria toxin and pseudomonas toxins work via ADP-ribosylation to decrease ________.
eEF2 (elongation factor) in ribosomal translation
What enzymes use biotin as a cofactor?
Carboxylases!
Pyruvate carboxylase
Acetyl CoA carboxylase
Propionyl CoA carboxylase
What enzymes need thiamine?
Pyruvate DH
Alpha KG DH
Transketolase
Branched chain ketoacid DH
(Decarboxylation)
What are the clinical manifestations of thiamine deficiency?
Wernicke-Korsakoff
Wet beri-beri
Dry beri-beri
What class of enzyme is niacin needed for?
Dehydrogenases
What is Hartnup disease?
Genetic deficiency in tryptophan transport in the gut and kidneys causing Pellagra-like symptoms
(tryptophan needed to make niacin)
What is the difference between uracil and thymine?
Uracil lacks a methyl
What enzymes require folic acid (THF)?
Thymidylate synthesis
Enzymes of purine synthesis
Acts as a 1 carbon carrier
What enzymes require B12? What pathway?
Homocysteine methyltransferase
Methylmalonyl CoA mutase
VOMIT pathway
B6 is needed for what processes/enzyme class?
Protein catabolism
Heme synthesis
-transamination-
How do B6-deficient RBCs appear?
Microcytic
Hypochromic
What are the clinical presentations of Riboflavin (B2) deficiency?
Cheilosis or stomatitis (cracking of scaling of lip and tongue)
Magenta-colored tongue
Blue sclera = ?
Osteogenesis Imperfecta
Bisphosphonates inhibit __________.
Osteoclasts
What cellular processes are Vitamin A used for?
Retinol/Retinoic acid: Cell division and turnover
Immune function
Retinal: vision (helps make rhodopsin)
What is the FIRST symptom of Vitamin A deficiency?
Night blindness
What is Vitamin A toxicity?
Teratogenic effects by interfering with homeobox genes -> limb and skeletal malformation
Note Vitamin A is a very common treatment for acne so make sure patients trying to get pregnant aren’t using it.
What enzyme needs Vitamin K? What does the enzyme do?
Gamma-Glutamyl Carboxylase
Gives prothrombin sufficient negative charge to initiate clotting via Ca++ bridging/binding to the negatively charged phospholipids.
INITIAL hemostasis is mediated by:
Platelets (in response to exposed/damaged collagen)
PT (prothrombin time) measures the ______ coagulation cascade.
Extrinsic
Which clotting factors need Vitamin K?
Factors 2, 7, 9, 10
Proteins C, S, Z
(a)PTT (activated partial thromboplastin time) measures the ______ coagulation cascade?
Intrinsic
What prevents clotting in a test tube?
Chelators of calcium:
Heparin, citrate, EDTA
If the lines Cross on a Lineweaver-Burke plots, then it is a __________ inhibitor.
Competitive
Cross = Competitive
If the lines do Not Cross on a Lineweaver-Burke plots, then it is a __________ inhibitor.
Non Competitive
Kinesin = _____grade transport.
ANTEROGRADE
What is the most common cause of alarming bloody nipple discharge?
Intraductal papilloma - proliferation of papillary cells with a fibrovascular core
Usually causes no masses or skin changes
What does the CFTR mutation cause?
Impaired post-translational processing of CFTR which is picked up by the ER and thus sent to the proteasome for degradation. It never even reaches the cell surface.
Mnemonic for remembering glycogen storage diseases from largest glycogen/earliest enzyme to smallest breakdown product and latest enzyme.
“McCo(n)Von”
5->3->1
Type 5: McArdle
Type 3: Cori
Type 1: von Gierke
What second messaging system does glucagon use?
Gs(alpha) -> adenylyl cyclase -> cAMP -> PKA
What pathways use cGMP and Protein Kinase G for signaling?
Smooth muscle relaxation among others
What is arginase deficiency and how does it present?
Arginase deficiency which is part of the urea cycle in the cytoplasm., generates orinithine and urea from arginine.
When it is deficient, arginine builds up in the cytosol and thus causes spastic diplegia, abnormal movements, and growth delay.
Unlike other urea cycle disorders, patients with arginase deficiency have mild or no hyperammonemia.
What are the acute, chronic, and teratogenic effects of Vitamin A toxicity?
Acute: nausea, vomiting, vertigo, blurred vision.
Chronic: alopecia, dry skin, hyperlipidemia, hepatotoxicity, hepatosplenomegaly, and visual difficulties.
Teratogenic: microcephaly, cardiac anomalies, fetal death
What does the PI3K/Akt/mTOR pathway do?
Intracellular signaling pathway important for anti-apoptosis, cellular proliferation, and angiogenesis. Mutations in growth factor receptors, Akt, mTOR, or PTEN that enhance the pathway activity can contribute to cancer pathogenesis.
What 3 major processes occur in the cytosol?
- Glycolysis
- Fatty acid synthesis
- Pentose phosphate shunt
What mutation occurs in HbC?
Missense mutation in beta globin gene for glutamate to lysine (a positive AA residue)
Gap junction = ? (protein)
Connexin
Tight junction = ? (protein)
Claudins, occludins
Desmosomes = ? (protein)
Cadherins
Hemisdesmosomes = ? (protein)
Integrins
What is methylmalonic acidemia?
Autosomal recessive organic acidemia (metabolic acidosis)
Complete or partial deficiency of methylmalonyl-CoA mutase
Results in hypoglycemia -> FFA metabolism and ketones -> worsening acidosis.
Organic acids directly inhibit the urea cycle leading to hyperammonemia.
What is the most common cause of Turner Syndrome?
Loss of paternal X chromosome
Function(s) of peroxisomes?
- Oxidation of very long (VLCFA) and branched-chain fatty acids
- Hydrogen peroxide degradation
Where does the TCA cycle, fatty acid oxidation, ETC, and apoptosis occur?
Mitochondria
What do lysosomes do?
Digest cellular debris and pathogens
Where does drug detoxification, lipid, phospholipid, and steroid synthesis occur?
Smooth ER
What is Zellweger Syndrome?
Defective peroxisomal biogenesis. Presents in early infancy with craniofacial abnormalities (widened sutures, large anterior fontanelle), hepatomegaly, profound neurologic deficits
Death occurs within months.
What is X-linked adrenoleukodystrophy?
Defective transport of VLCFAs into peroxisomes. Patients present in childhood or adulthood with neurologic deterioration and adrenal insufficiency.
In large doses, Vitamin E acts like ________.
Vitamin K, thus high Vitamin E intake in patients on Warfarin can be risky
Vitamin ___ is an antioxidant and is especially vital in RBCs protecting against free radical formation. Vitamin ___ is also an antioxidant.
E, C
How does caffeine increase glucose levels?
Methylxnathines decrease phosphodiesterase activity in the liver.
What is the sequence of events when epinephrine binds smooth muscle cells (incl. receptor)?
Epinephrine -> alpha 1 adrenergic receptor -> Gq -> Phospholipase C -> PIP2 cleaved to DAG and IP3 -> IP3 releases Ca from smooth muscle ER
What does lysyl oxidase do?
Oxidizes OH-Lys to enable collagen crosslinks in the extracellular space.
What enzyme converts glucose to G6P in the liver? What controls it?
Glucokinase
Hormonally controlled by insulin
______ converts F6P to F16BP in glycolysis.
PFK 1
Requires 1 ATP
__________ converts PEP to Pyruvate in the last step of glycolysis.
Pyruvate Kinase
What are the clinical manifestations of pyruvate kinase deficiency?
- Hemolytic anemia
- Increased BPG
- No heinz bodies
PFK2 exists ONLY in _____. What does it do?
The liver. Drives glycolysis into fatty acid synthesis.
BPG binds to the _______.
beta subunits
Accumulation of what substance (and using what enzyme) causes cataracts in a genetic deficiency?
Galactose gets converted to galactitol beneath the lens via Aldose Reductase
What happens in a galactokinase deficiency? In uridyl transferase deficiency?
Galactokinase: cataracts early in life
Gal 1-P uridyltransferase deficiency: Cataracts early in life, vomiting, diarrhea, lethargy, liver damage, hyperbilirubinemia, mental retardation
WHY? Gal 1-P uridyltransferase is further down the galactose breakdown pathway and is at this point trapped in the liver and thus metabolites build up.
What is the most common GI complication of Down Syndrome? Secondary problems?
Duodenal atresia
Tracheoesophageal fistula, celiac, imperforate anus, Hirschsprung disease
Where does collagen synthesis take place? And where is the Vitamin C step
Begins in the nucleus and is completed in the Rough ER where post-translational modifications of proline and lysine hydroxylation occur (with Vit C as a cofactor)
What substance is defective in Ehlers-Danlos?
Collagen Type V
What substance is defective in Osteogenesis Imperfecta?
Collagen Type I
What are the physical findings of Trisomy 18?
Micrognathia Prominent Occiput Low set ears Clenched hands with overlapping fingers Heart defects (esp VSD) Rocker-bottom feet Horsehoe kidney Meckel's diverticulum
What are the physical findings of Trisomy 13?
Midline facial defects (e.g. holoprosencephaly, cleft lip)
Omphalocele
Polydactyly but NOT overlapping fingers
What is the Haldane effect in oxyhemoglobin saturation and what is the benefit?
As PO2 rises (i.e. as hemoglobin gets O2 saturated), PCO2 and H+ get unloaded.
H+ stabilizes the deoxy-Hb
What causes cataracts in diabetic patients?
Excess glucose converted to sorbitol.
Fructose 1P + aldolase B enzyme yields?
DHAP and glyceraldehyde
What cofactors and coenzymes does PDH (pyruvate dehydrogenase) need to work? +mnemonic!
Tender Loving Care For Nancy
Thiamine**** Lipoic acid CoA FAD(H2) from riboflavin NAD(H) from niacin or tryptophan
What is the histological progression of ischemic stroke?
12-24 hours: “Red neurons” (eosinophilia, pyknotic nuclei, loss of Nissl substance)
24-72 hours: Neutrophil infilatration
3-7 days: Macrophage/microglia infiltration and phagocytosis
1-2 weeks: Reactive gliosis and vascular proliferation (macroscopically liquefactive necrosis)
> 2 weeks: glial scar formation (cystic area surrounded by dense glial fibers after 1 month)
When and how does congenital hypothyroidism present?
Around 2 months after maternal T4 wanes (normal at birth)
Lethargy Hypotonia Enlarged fontanelle Protruding tongue Umbilical hernia Poor feeding Constipation Dry skin Jaundice
If not treated, irreversible intellectual disability can occur
How does Acute Intermittent Porphyria present? What enzymes are deficient or nonfunctional?
Neurologic symptoms and acute abdominal pain but NOT photosensitive
PBG deaminase deficiency
OR
ALA synthase down regulation (due to meds, alcohol, smoking, low cal diet, or puberty)
What is Alkaptonuria? How does it present?
Autosomal recessive disorder of tyrosine metabolism.
Deficiency of Homogentisic acid dioxygenase causing an accumulation of Homogentisate
Urine will turn BLACK if left in the toilet/given time to oxidize
BLUE-BLACK deposits often found in sclerae and ears
Arthritis later in adulthood
What is Homocystinuria? How is it inherited?
Autosomal recessive
Error in methionine metabolism: Deficiency in Cystathione beta-synthase an enzyme that requires *Pyridoxine (Vitamin B6) as a cofactor
^tx with pyridoxine generally helps reduce plasma homocysteine levels
How does Homocystinuria present clinically?
Age 3-10
Ectopia (dislocated) lens
Intellectual disability
Marfanoid habitus
Morbidity: thromboembolic events increased
How do fibrates work? What is a potential side effect?
Fibrates upregulate lipoprotein lipase (increasing fatty acid oxidation) AND INHIBIT cholesterol 7alpha-hydroxylase which synthesizes bile acids
Together this causes an accumulation of cholesterol in the gallbladder and often causes cholesterol stones.
What complex in the ETC does Cyanide inhibit? What its other name? Via what metal?
Complex IV aka Cytochrome C oxidase.
Cyanide binds Fe3+ and prevents it cycling back to Fe2+ and stopping electron transport.
What antidotes are given to treat Cyanide poisoning?
Nitrite, an oxidizing agent. It will take electrons from Fe3+ and make Fe2+. Purposely make methemoglobin (HbFe3+) as sacrifice
OR
thiocyanate
OR
Vitamin B12
What complex in the ETC does CO inhibit? What its other name? Via what metal?
Complex IV aka Cytochrome C oxidase.
CO binds Fe2+ and competitively inhibits Oxygen binding
How does oligmoycin block the ETC?
Blocks the F0 (transmembrane) portion of the ETC protein
What are weak uncouplers of the ETC?
2,4-DNP + H+
Aspirin (high doses)
Thermogenin (brown adipose)
What controls the rate of the ETC (respiratory control)?
The ATP/ADP translocase antiporter
What enzyme is deficient in Von Gierke’s disease?
Glucose-6-phosphatase
What enzyme is deficient in Pompe’s disease?
Lysosomal alpha1,4-glucosidase
What enzyme is deficient in Cori’s disease?
Glycogen debranching enzyme
Failure at alpha1,6 branch
What enzyme is deficient in Andersen’s (Type IV) disease?
Branching enzyme
What enzyme is deficient in McArdle’s disease?
Muscle glycogen phosphorylase
M McCardle, M muscle
What enzyme is deficient in Her’s (Type VI) disease?
Hepatic glycogen phosphorylase
H Hers, H hepatic
What glycogen storage disease presents with cardiomegaly?
Pompe
What is the mnemonic for Andersen and Cori disease?
“ABCD”
Andersens = branching enzyme Coris = debranching enzyme
What are the 2 AAs that are ONLY ketogenic (not glucogenic)?
Lysine and leucine
What does fomepizole do and why is it used?
Inhibits alcohol dehydrogenase
Used to treat methanol poisoning
What does disulfuram do and why is it used?
Inhibits acetaldehyde DH.
Used to treat alcoholism
What are the 3 main features of G6PD deficiency?
- Immunodeficiency
- Heinz bodies
- Hemolytic anemia
What is the treatment for methemoglobin?
Methylene blue, a reductant
What does glutathione protect against?
H2O2 Oxidant stress (infection, drugs, fava beans)
How is G6PD deficiency inherited?
X-linked recessive
What is a hint that there is cyanide poisoning?
“Odor of bitter almonds”
What are the initiators of the extrinsic apoptotic pathway?
TNFR1 (tumor necrosis factor 1)
AND FasL
What are the initiators of the intrinsic apoptotic pathway?
Pro-apoptotic: Bax, Bak, Bim
Anti-apoptotic: Bcl-2 and Bcl-x
Both intrinsic and extrinsic apoptotic pathways converge at what pathway point?
Caspases
Caspase is a nickname for “cysteine-aspartic acid proteases” which is how they effect killing.
What enzyme deficiency is seen in Ehlers-Danlos syndrome?
Deficiency in procollagen peptidase:
An enzyme that cleaves terminal propeptides from procollagen in the extracellular space. -> this collagen is too soluble and doesn’t properly crosslink.
What are the mutations associated with early onset and late-onset familial Alzheimer’s disease?
Early:
- Amyloid precursor protein (APP) on Chromosome 21
- Presenilin 1 on 14
- Presinilin 2 on 1
Late:
ApoE4
What is the direct source of Acetyl CoA for FA synthesis?
Citrate!
PDH generates Acetyl CoA in the mito but there is no transporter out to the cytoplasm where FA synthesis occurs, so first Acetyl CoA enters the Kreb’s cycle in the mito to make citrate and Citrate is then transported to the cytoplasm.
What are the two sources of NADPH for FA synthesis?
- Pentose Phosphate Shunt
2. Malic enzyme (malate -> pyruvate)
What does Acetyl CoA carboxylase do?
Converts acetyl CoA to malonyl CoA to begin FA synthesis.
Requires biotin + ATP
Humans have no desaturase that can go beyond Carbon __. What is the significance?
9.
We have two essential fatty acids: Linoleic and Linolenic acid (two double bonds after 9)
Longterm alcoholism or short term binge drinking causes an accumulation of _______ due to alcohol’s inhibition of ______.
Triglycerides
VLDL
Once ____ cells in the liver scar it, alcoholic fatty liver disease becomes irreversible.
Ito
Apo A = activator of ____
LCAT
Apo B and E are both involved in _____-______ interactions.
Receptor-lipoporotein
Apo C = activator of _______
LPL
lipoprotein lipase
Chylomicrons contain MOSTLY ____ and some ____. On their surface they express:
Mostly TAGs
Some CEs
Apo B48 on the surface.
What is abetalipoproteinemia?
Defect in Apo B48 (chylomicron receptor) preventing the intestine from absorbing fats (and fat soluble vitamins).
Characterized by abnormal growth and severe disease, fatty stools.
What defect causes dysfunctional LDL receptor gene expression? How is it inherited?
Familial Hypercholesterolemia Type IIa
Autosomal DOMINANT
What are the possible defects in Familial Hypercholesterolemia Type I? How is it inherited?
What is the pathognomonic finding?
Deficiencies in LPL (lipoprotein lipase) OR Apo C which turns on LPL
Autosomal recessive
Red-orange eruptive xanthomas
Xanthomas of the achilles tendon or knuckles
Or corneal arcus = ?
FH Type IIa (the Autosomal dominant LDL receptor one)
Where does HMG CoA reductase function?
What 3 things control its function?
ER
Insulin turns on
Glucagon and statin drugs turn off
What enzyme makes bile acids in the liver?
7 alpha hydroxylase
What is a major side effect of statins? Why?
Muscle pain
Farnesyl PPi is a downstream intermediate of cholesterol synthesis and is needed to make Coenzyme Q in the ETC.
So block of HMG CoA reductase ultimately blocks Coenzyme Q/ETC.
How does cholestyramine work?
Binds bile acids and prevents their reabsorption -> 7alpha hydroxylase in the liver will start using up excess cholesterol to make new bile acids.
N-acetylgalactosamine is an example of what class of sphingolipid?
A hexosamine
N-acetylneuaminic acid is an example of what class of sphingolipid?
A sialic acid
How do you tell Tay-Sachs form Niemann-Pick since they both can have a cherry red spot?
Tay-Sachs will have psychomotor retardation.
Niemann-Pick will have foamy macrophages
What are the sphingolipid diseases? What are their deficient enzymes and accumulating inclusion bodies?
Sphingolipidoses = defect in single lysosomal enzyme
- Tay-Sachs - Hexosaminidase A, Ganglioside GM2
- Gaucher - Glucocerebrosidase, Glucocerebroside
- Sphingomyelinase, Sphingomyelin
What is the hallmark of Gaucher’s disease?
“Crumpled paper inclusions”
What is the defect in I-cell disease and how does it present?
Defect in M6P phosphotransferase so that ALL lysosomal enzymes are absent -> leads to inclusion bodies of all kinds of junk instead of just 1 type.
What are the 2 major mucopolysaccharidoses
Hunters and Hurlers
After AAs are broken down, what is the fate of the amino group (ammonia NH3+)?
- Disposed of by the liver in urea
OR - Disposed of by the kidney in the urine (NH4+)
Does urea change the pH of blood?
No, thats why its made! Contains neutral NH2 instead of NH3+!
What is the major (blood) transport form of ammonia?
Glutamine
What are the two sources of N to make urea?
Glutamine and Aspartate
AST/ALT > 1 =?
alcohol abuse
What is the obligate activator to turn on carbamoyl phosphate synthetase I (urea cycle) after a high protein meal?
N-acetylglutamate
What is the obligate activator for Pyruvate Carboxylase to function?
Acetyl CoA
What are the 2 possible defective enzymes in the urea cycle and what are their inheritance patterns? How do you tell them apart?
Carbamoyl phosphate synthetase (AR) - NO orotic aciduria
Ornithine transcarbamoylase (XR) - OROTIC ACIDURIA
Pink/red “port wine” urine =
Black urine =
Brown urine =
Caramel/burnt orange =
Pink urine = Porphyria
Black urine = Alkaptonuria
Brown urine = Hyperbilirubinemia
Caramel/burnt orange = MSUD
What is the mnemonic to remember the 5 things that generate propionyl CoA?
VOMIT pathway (Amino acid ctabolism)
Valine Odd-carbon FA Methionine Isoleucine Threonine
What does methylmalonyl CoA mutase do? What cofactor does it require?
Converts methylmalonyl-CoA
to succinyl CoA
Requires B12
Homocysteine methyl transferase requires what to function?
What does it do?
THF
B12
Converts homocysteine to s-adenosylmethionine (SAM)
What does Cystathionine Synthase do? What does it require?
Converts homocysteine to Cystathionine
B6
THF is one ____ donor.
Methyl (carbon)
other names based on where the 1 carbon is: formyl, methenyl, methylene
Methyl THF is the _______ pool.
Storage
Must be regenerated to THF via Homocysteine methyl transferase (B12) in order to be used in the active folate pool.
What is the synthesis pathway of tyrosine to catecholamines and what are the cofactors?
Tyrosine +THB -> dopa +B6 -> Dopamine +VitC/Cu2+ -> Norepi +SAM -> Epi
What are the 2 locations of heme synthesis?
- Liver
2. Enucleated RBC
How are the porphyrias inherited?
Autosomal dominant!
What should you never give to someone with porphyria?
A barbiturate because it upregulates ALA synthase
How can ferrochelatase be dysfunctional? What happens?
Acquired porphyria:
- Inhibited by lead (poisoning)
- Requires Fe2+ to function (iron deficiency)
- Genetic
Protoporphyrin builds up and then absorbs Zn (which makes it fluorescent!)
Hemochromatosis causes _____ deposits to accumulate in the liver, pancreas, joints, and skin.
Hemosiderin (ferritin with excess Fe in it)
The accumulations cause cirrhosis, diabetes, arthritis, and dermatitis (BRONZE appearance!!)
Color:
Heme is ____
Biliverdin is _____
Bilirubin is _____
Heme = purple Biliverdin = green Bilirubin = orange
What is Crigler-Najjar syndrome?
Genetic defect in UDP-glucuronyltransferase
Incompatible with life
What is Gilbert syndrome?
Benign deficiency in UDP-glucuronyltransferase.
Only causes jaundice under periods of stress
What drug do you give infants who are still jaundiced after blue light if they’re showing signs of kernicterus?
Phenobarbital
Baby presents with orotic aciduria, how do you tell urea cycle defect from pyrimidine synthesis defect?
If there is no hyperammonemia, it is pyrimidine synthesis defect.
Methotrexate, Trimethoprim, and Pyrimethamine all inhibit:
Dhihydrofolate reductase (needed to regenerate THF)
SCID is a defect in:
Adenosine deaminase
part of the purine salvage pathway
Gout is a defect in:
Xanthine oxidase
Takes xanthine from purine salvage pathway to make uric acid.
Acute tx of gout:
Chronic tx of gout:
Acute = colchicine Chronic = allopurinol or probenecid
What enzyme does 6-mercaptopurine inhibit?
Amidotransferase (IMP/GMP -> AMP) in the purine salvage pathway
Remember with megaloblastic anemia it’s not always B12 or folate deficiencies. Anything that affects DNA synthesis will yield similar results.
e.g. orotic aciduria, so you may give uridine to bypass UMP synthase
What’s another term for mucopolysaccharides?
Glycosaminoglycans
Sudan black and Oil Red O stain for ______.
Lipids
Corneal clouding =?
Mucopolysaccharidoses
Which RNA polymerase synthesizes rRNA?
RNA Pol I
Which RNA polymerase synthesizes tRNA?
RNA Pol III
Which RNA polymerase synthesizes mRNA, snRNA, and miRNA?
RNA Pol II (II is TOO strong and does the heavy lifting)
What does RT-PCR test/amplify?
mRNA
What is linkage disequilibrium?
When two unlinked genes are in close proximity and then appear linked (i.e. occur together more often than you would expect).
___________ is also known as lecithin is a component of pulmonary surfactant and will greatly rise in secretion during the 3rd trimester when Type II pneumocytes secrete it precipitously.
___________ is a common membrane phospholipid. The L/S ratio is roughly 1:1 until it reaches 2:1 at 35 weeks gestation, indicating lung maturity.
Phosphatidyl choline
Sphingomyelin
_______ is the only RNA that replicates within the nucleus.
Orthomyxovirus (e.g. influenza)
Antigenic drift =?
Antigenic shift = ?
Drift = point mutation in H or N (why we need the flu vaccine every year, causes epidemics)
Shift = SEGMENT assortment (often between different species), causes pandemic
______________ syndrome is characterized by loss of speech and motor skills, deceleration of head growth, and stereotypic hand movements after a period of normal development. It affects mainly girls and is associated with mutations in the MECP2 gene.
Rett Syndrome
What defect is seen in Familial Hypocalciuric Hypercalcemia?
Defective calcium sensing receptor in the parathyroid gland and the kidneys. Higher serum calcium levels are required to suppress the secretion of PTH.
Mild asymptomatic hypercalcemia, reduced urinary excretion of calcium, mildly elevated PTH.
Which triglyceride med can cause precipitation of gout?
Niacin
What are the symptoms and lab values of hyperaldosteronism?
Hypernatremia
Hypokalemia
Metabolic alkalosis -> paresthesias and muscle weakness
Which dyslipidemia syndrome is associated with a number one risk of acute pancreatitis?
Familial chylomicronemia Type I which is caused by a deficiency in LPL resulting in large chylomicrons staying in the blood -> hypertriglyceridemia, acute pancreatitis, and lipemia retinalis (milky appearing retinal vasculature)
How does TNF alpha cause insulin resistance?
Through serine kinases that phosphorylate the beta (intracellular) subunits of the insulin receptors.
What is pseudohypoparathyroidism?
Genetic disorder where kidneys are insensitive to PTH. Leads to hypocalcemia and hyperphosphatemia BUT ALSO
the PTH will keep pumping out hormone to try and correct this causing massive bone resorption: shortened 4th and 5th phalanges and stunted bone growth.
If a patient gets diabetes insipidus from lithium but truly NEEDS their lithium so it can’t be discontinued, how can you “trick” the body into maintaining sodium levels?
thiazide +/- K+ sparing diuretic or indomethacin (NSAID)?
A mild diuretic will cause just enough volume depletion to “Scare” the body into increasing sodium reabsorption in the proximal tubule. Therefore enough sodium is reabsorbed before it ever reaches the DCT/collecting duct where ADH can screw things up.
Indomethacin works by reducing renal blood flow
If a postpartum woman presents with failure to lactate, what are two endocrine explanation?
Sheehan Syndrome: infarction of the pituitary gland (due to intrapartum bleeding, poorly oxygenated portal blood, or demand ischemia for the active pituitary).
Could also be hypothyroidism
What is the pathogenesis of diabetes causing neuropathy?
Osmotic damage. Glucose is normally pumped into cells and converted to sorbitol so that the glucose concentration gradient is maintained. However if sorbitol DH (which breaks down sorbitol to fructose) is overwhelmed, sorbitol accumulates -> draws in water damaging Schwann cells.
This is similar to the pathogenesis of retinopathy: sorbitol in the lens causes swelling
What is the FIRST thing you should give a person presenting with DKA?
IV SALINE! hydration hydration hydration
THEN you can give IV insulin
and THEN be ready to replace K+ IV if needed
Hyperosmolar Hyperglycemic State (HHS) usually occurs in type ___ diabetics and is characterized mainly by severe ____.
DM Type 2
Severe dehydration
How do the fast-acting insulins work to be faster than endogenous/regular insulin?
The C terminals of the insulin B chain have altered AAs that prevent polymerization and allow rapid absorption from the injection site.
Regular insulin forms hydrogen bonds and hexamers with zinc ions that delays their absorption when given subcutaneously.
_____ syndrome leads to small and firm testes with hyalinization that leads to sertoli and leydig cell damage -> decreased FSH and LH.
Klinefelter
SIADH will present with apparent ___volemia and ____natremia
Euvolemia and hyponatremia
To get rid of all the excess water, aldosterone is lowered in hopes of salt-wasting and water following. This usually is successful and helps reach euvolemia but it worstens the hyponatremia
Intracellular receptors include:
Fat-soluble hormones (steroids)
Fat-soluble vitamins
Thyroid hormone
DeQuervain’s thyroiditis aka ?
It generally follows what?
Subacute GRANULOMATOUS thyroiditis
(i.e. on histology you will see granulomas/multinucleated giant cells)
Generally follows an acute viral illness
Necrolytic Erythema Marginatum = ?
Glucagonoma
