Biochem, Congenital Conditions, and Cancers Flashcards
Retinoblastoma
Loss of Rb, allowing for E2F to activate transcription Autodominant, sporadic/familial
Patient has familial history of osteosarcoma, rhadbomyosarcoma, breast, and brain cancer. Condition? Mechanism?
Li-Fraumeni Syndrome: Loss of hetero of p53; AUTODOMINANT
Chromosome 17
Familial Adenomatous Polyposis
APC w/t makes a destruction complex for Beta catenin thus silencing the Wnt pathway. Loss of gatekeeper causes hyperactivation of Wnt pathway think APC is an army transport for the beta catenin (swords are in army)
Von Hippel Lindau Syndome
Loss of VHL protein which normally targets Hypoxia Inducible Factor 1alpha for ubiquination and degredation. Loss causes Increased HIF levels vHippel L increases HIF levels Risk for Hemanigioblastomas of Cb, Pheos, Renal cell carcinoma (clear cell)
Hereditary non-polyposis colonrectal cancer
Lynch Syndrome due to loss of DNA mismatch repair
Wilms tumor on chromo?
WT-1 on Chromo 11
MEN 1, 2a, 2b
MEN 1: OM3p–Pituitary (prolactin/ACTH), parathyroid, pancreas (panc is a GASTRIN secreting tumor***)
MEN2a: 1M2P–medullary thryoid cancer (calcitonin), pheo, parathyroid
MEN2b: 2M1P–Medullary thryoid (calcitonin), mucosal neuramata (oral), pheo, Marfan like body (tall–abraham lincoln)
Carcinomas that spread hematogenously
Renal Cell Carcinoma, Follicular Thyroid Carcinoma, Hepatocellular Carcinoma, Choriocarcinomas
Standard Deviation
1 STD
2 STD
3 STD
1) 68
2) 95 (+27 each side)
3) 99.7 (+4.5)
Hartnup’s Disease: mechanism? deficient in? symptoms?
Defective renal/GI absorption of Tryptophan: need for Melanin (hypopigmentation/sunburn), nicotininc acid (Pellagra from niacin def) and serotonin.
Patient will have aminoaciduria of neutral amino acids
Stains:
Vimentin?
Desmin?
1) Connective Tissue
2) Muscle
Cofactor needed for Transketolase?
Transaminase?
Thiamine (B1)
Pyridoxine (B6)
Which AA donates NH3 in urea cycle?
What starts cycle?
What is rate limiting enzyme?
Aspartate
N-acetyl glutamate
Carbamoyl Phosphate Synthase I
Diaper Smelling like burnt sugar
Maple Syrup Urine Disease: cannot break down branched chain AA (leucine, isoleucine, valine).
Broken Branched chain alpha ketoacid dehydrogenase def, pyruvate dehydrogenase, alpha ketoglutarate dehydrogenase.
Cofactors: TLCFN (“Tender love and care for no-one)
Thiamine, Lipoate, CoA, FAD, NAD+
Co factors required for branched chain AA degradation
Complex: branched chain alpha ketoacid dehydrogenase.
Cofactors: Tender loving care for Nanny
Thiamine, Lipoate, CoEnzyme A, FAD, NAD
Enzyme needed to make Serotonin?
Cofactor? Cofacor produced by? What else is it used in?
Tryptophan hydroxylase (requiring BH4 made by Tetrahydrobiopterin reductase)
Taking Phenylalanine to Tyrosine and then to DOPA
Tetrahydrobiopterin enzyme used to make?
Whihc is used in?
BH4
Dopa, Tyrosine, Serotonin, and NO
Enzyme that converts procarcinogens into carcinogens?
Microsomal Monoxygenase
(can be Bilateral) renal tumors of blood vessels, muscle, and fat: Condition? Associated with what else?
TSC: Autodominant.
Bilateral renal Angiomyolipoma, Brain Harmatomas (causing seizures/mental retardation), and ash leaf skin patches
Cerebellar Hemangiomas and Liver Cysts: condition?
Associated with what else?
von Hippau Lindau (defect in vhl protein that inhibits HIF)
Bilateral renal cell carinoma
Capillary Angiomas of the face and choriod?
Sturge Weber Syndrome. “weber wine”
Facial port wine stain and leptomeningeal capillary-venous malformations.
Multiple telangectasia of mucosa and skin?
Hereditary hemorrhagic telangectasias (Osler-Rendu-Weber).
Recurrent epistaxis and GI bleeding (melena)
Zero Order kinetics?
First Order Kinetics?
Zero Order=same amount of drug (ie 10mg)–occurs when removal system is saturated
First order= proportion of drug (ie 50%)–usually is linear on graph and tends to occur before clearance is saturated
Dark Connective Tissue with brown pigmented sclerae, urine turns black with prolonged exposure to air: Cause? Enzyme? Other findings?
Alkaptonuria (ochronosis): def of homogentisate oxidase.
Can’t degrade tyrosine to fumarte.
Can have debilitating Arthalgias (homogenitistic acid is toxic to cartilage)
Riboflavin (B3) is a cofactor for?
FMN and FAD which are used in the TCA cycle.
FAD is used for Succinate dehydrogenase which takes succinate to fumarate
Non Insulin Dependent Glut’s? Location?
Liver/Panc cells?
Skeletal Muscle?
Glut 1/3 in brain
Glut2
Glut4 (insulin dependent)
Clinical Consequence of a glycolytic enzyme def?
Hemolytic Anemia (pyruvate kinase def)
Rate limiting enzyme for:
- Glycolysis
- Gluconeogenesis
- TCA
- Urea Cycle
- De novo purine
- De novo pyrimdine
- PFK1
- Fructose 1,6 bisphosphatase
- Isocitrate dehydrogenase
- Carbamoyl Phosphate synthase I
- PRPP (glutamine phosphoribosylpyrophate amidotransferase)
- Carbamoyl Phosphate Synthase II
Cori Cycle?
Lactic acid produced by muscles goes into blood and goes thru gluconeogenesis to get to turned into glucose (pyruvate is intermediate in both muscles and liver)
Pyruvated Dehydrogenase Complex cofactors?
TLC for noone.
“Thiamine (B1), Lipoic Acid, CoA (from B5), FAD (B2), NAD (B3)”
Which cell cannot use Ketones? Why?
RBCs cannot use Ketones because they lack MITOs
(Brain can use Ketones)
Newborn with anion gap ketoacidosis and hypoglycemia with increased propionic acid in urine?
Congential Propionyl CoA carboxylase deficiency (same thing inhibited with B7 def from too many egg whites=Dermatitis, allopecia, Enteritis)
Propionyl CoA–>Methylmalonyl CoA (via P CoA carb w/ Biotin)
Weakness, Lethargy, Hypoketotic Hypoglycemia:
Deficiency? What builds up?
Most likely Carnitine Acyl Transferase Deficiency (Fatty acid metabolism).
Long chain fatty acids from inability to bring long chain fatty acids into mitochondria
Amino acids in:
- Essential AA
- Nuclear Localization Signal
- Branched (disease associated with?)
- Ketogenic
- Basic?
- Present in Histones
- Acidic?
- PVT TIM HALL
- Lysine Arginine Proline (LAP for NLS)
- Isoleucine, Leucine and Valine (Maple syrup urine disease)
- Lysine and leucine (L with K)
- Lysine, Arginine, and Histidine
- Arginie and Lysine in Histones (cuz they are positive so that the negative charge can stick)
- Aspartate and Glutamate
What is the precursor for:
- Thyroxine
- Niacin
- Porphyrin (Heme)
- GABA
- Urea
- NO
- Creatine
- Glutathione
- Histamine
- Serotonin
- Melanin
- Thyroxine: Tyrosine
- Niacin: Tryptophan
- Porphyrin(Heme): Glycine
- GABA: Glutamate (requires B6; why b6 def = tetany)
- Urea: Arginine
- NO: Arginine
- Creatine: Arginine
- Glutathione: Glutamate
- Histamine: Histadine
- Serotonin: Tryptophan
- Melanin: Tyrosine
Orotic Acid in blood/urine?
Conditions (2) Presentations?
Deficient enzyme used in?
Other presenting symptoms?
Tx?
1) Ornithine Transcarbamylase deficieny (OTC): hyperammnoemia with decreased BUN
2) Orotic Aciduria=MEGALOBLASTIC ANEMIA: (x UMP synthase = no pyrmidine synth pathway); Used in urea cycle to pull ornithine and carbmoyl phophaste from mito and combine them into citruline in cytosol. TX: URIDINE**** (a cause of megaloblastic anemia where you don’t use follate)
Decreased BUN (no urea production), sxs of hyperammonia.
Purine vs Pyridimine synthesis
Purine: “Ppl who are pure wait for the ring”. Sugar then add PRPP (ring)
Pyrimidines: take the ring and build the sugar on it
Drug that inhibits:
Thymidylate synthase
Inosine Monophosphate dehydrogenase
PRPP synthetase
- Thymidylate synthase: 5-floururacil
- Inosine Monophosphate dehydrogenase: Mycophenylate/Ribavirin
- PRPP synthetase: 6-mercaptopurine
Eukaryotic DNA Polys:
- Lagging Strand
- DNA Repair
- Mito DNA Rep
- Leading Strand
- Lagging Strand: Alpha
- DNA Repair: Beta, Epsilon
- Mito DNA Replication: Gamma
- Leading Strand: Delta
Enzymes Required to convert Phenylalinine to DOPA
Phenylalinine Hydroxylase
Tyrosine Hydroxylase
Dihydropterin Reductase (generates BH4)
Enzyme broken in?
Albinism
PKU
Alkaptonuria
Tyrosinase
Phenylalinine Hydroxylase or _Decreased tetrahydrobiopterin cofactor (will see neuro issues and increased prolactin after several weeks on the PKU diet). _
Homogentisate Oxidase
Lens subluxation?
Tx?
Homocysteinuria–can give Pyridoxine (cofactor for cystithione synthase, with restriction of methionine and supplemenation of cyestine these improving whatever function they do have)
Marfan’s Syndrome–no tx
Neutral AA transporter Def:
Causes what?
Hartnups
Loss of neutral AA’s in gut and renals
Tryptophan cannot be made into Niacin and you get Pellegra
vitamin A tox?
Visual Impairment, fatigue, Ataxia, Increased Cerebral Pressure (pseudotumor cerebri)
Brittle Kinky hair, growth retardation and hypotonia; general failure to thrive in 6 month old
Menkes Disease: impaired coper absorption and trasnport causing defect in lysyl oxidase (copper cofactor)
Chromosome location of these AUTO DOM diseases:
- PKD1
- PKD2
- APC
- Huntigton Disease
- NF1
- NF2
- vHL
All ARE AUTODOMINANT**** cuz they are tumor suppressors (HD isn’t)
- 16
- 4
- 5
- 4
- 17 (AUTODOM)
- 22
- 3
Chromo for Cystic Fibrosis? Defect? What type of Channel is it?
Cri du chat?
Williams Syndrome
Chromo 7; Misfolded FUNCTIONAL protein that gets ubquinated and destroyed; ABC (ATP binding cassette) Chloride channel
5
7
3 pathways that take place in mito and cytosol?
HUG
Heme synthesis, Urea cycle, GLUCONEOGENSIS
Krabbe’s Disease
Enzyme? Build up? Dominance? Sxs?
AutoRec
X Beta-Galactocerbrocidase.
Accumlation of Galactocerbroside
Peripheral Neuropahty, Devo Delay, Globoid Cells and Optic Atrophy
Niemann-Pick Disease
Enzyme? Build up? Dominance? Sxs?
Auto Rec (all auto rec except for Fabrys, Hunters)
X sphingomyelinase
Accumulation of Sphingomeylin
Hepatosplenomeagly, progresive neurodegeneration, faom cells, cherry -red spots on macula
Ashkenazi Jews
Hurler’s Syndrome
Enzyme? Build up? Dominance? Sxs?
Auto Rec
Mucopolysaccharidoses
X Alpha L-iduronidase (“Hurler has an L in it”)
Heparan sulfate and dermatan sulfat accumulation
Gargoylism, corenal clouding, hepatosplenomegaly, airway obstrction deve delay
Meachrmoatic Leukodyrstophy
Enzyme? Build up? Dominance? Sxs?
Auto Rec
Sphingolipidoses from X Arylsulfatase A
Accumulation of Cerbroside sulfate
Dementia, ataxia (PNS and CNS demyelination)
Hunter’s Syndrome
Enzyme? Build up? Dominance? Sxs?
X-linked recessive mucopolysaccaraharidoses
X iduronate sulfatase
Accumulation of heaparan sulfate and drmatan sulfate
(less severe form of hurler’_
Associated with agressive behaivairo and NO CORNEAL CLOUDING (“hunter’s are agressive and need to see”)
Gaucher’s Disease
Enzyme? Build up? Dominance? Sxs?
Lysosomal stoarge disease (sphingolipidosis)
Autorec
x Glucocerbrosidase causing acumulation of glucocerbroside
Hepatosplenomagely, bone crises, aspectic ncerosis of femur.
“Gaucher cells”= macrophages looking lice crumpled paper
Tay-Sachs Disease
Enzyme? Build up? Dominance? Sxs?
Auto Rec sphingolipidisose
Def of hexasaminase A
Accumlation of GM2 ganglioside
Progerssive neurodegeneration, lysosomes with onion skin, cherry red spot on macula
NO HEPATOSPLENOMEAGLY (contrast wiht Neimann pick)
Fabry’s Disease
Enzyme? Build up? Dominance? Sxs?
X link rec sphingolipdosis
X alpha galactosidease A
Accumulation of ceramide trihexidose
Angiokeratomas, HEART and RENAL FAILURE, perihperal neuroaphty
“Can’t to FABRICATE heart and kidneys using ceramide triheixose”
Megaloblastic anemia not treated with Folate or B12?
Orotic Aciduria. Tx with Uridine. (NOT OTC)
Farber’s Disease
Ceramidase Def, causing build up of ceramides in skin (granulomas) and neurons
DPC gene?
Deletion predisposes risk for Pancreatic Cancer.
Mental Retardation syndrome seen almost exclusively in girls? Why? Associated?
Rett Disorder. X linked dominant (males almost always die in utero). Stereotyped hand wringing is associated.
“There aint no Bret’s with Retts”
Glycerol Kinase? Location?
LIVER***
TAGs broken into Glyercol and Fatty acids.
Glyercol is then phophorylated by glycerol kinase into DHAP to be used into glycolysis/gluconeogensis.
Mitochondrial Poisons: name and what they inhibit?
“RACO 1,3,4,5”
Rotenone (Complex I: NADH–>NAD)
Antimycin A (Complex 3/CoQ)
CO and Cyanide (Complex 4: H2 + O–>H2O)
Oligomycin (Complex 5: ATP synthase)
ASPIRIN AND 2,4 Dinitrophenol are uncoupling agents (thermogenic like brown fat)
Child biting lip and self mutilating: condition?
Whats broken? Part of what pathway?
What enzyme is hyperactivated and what builds up?
Lesch Nyhan Syndrome
HGPRT: purine pathway
PRPP aminotransferase hyperactive producing too much PRPP (all this is upstream of HGPRT; PRPP builds up as its not used by HGPRT during salvage and so PRPP aminotransferase uses it to make 5-phopsphoribosylamine)
Enzyme that converts NE to E? Cofactor?
PNMT (phenyethanolamine) requiring SAM as cofactor
Rate Limiting steps in 1) Purine and 2) Pyrimidine Synthesis
1) Glutamine PRPP aminotransferase
2) Carbamoyl Phosphate synthase II
High levels of HMP/PPP pathway can be seen in liver and adrenals, why?
NADPH is need for cholesterol synthesis
RNA polymerases each make?
“RMT”: 1) bRent, 2) Matt, 3) Tom
1) Ribo Rna
2) mRNa
3) tRNA
What accumulates with Methotrexate use?
Dihydrofolate polyglutamase precursor for DHFR
Inability to oxidize very long chain fatty acid is defect in what organelle?
Perioxisome
What cofactor should you think about when you hear an amino acid being combined with something from the TCA cycle/alpha ketoglutarate
B6
What cycle does the brain use to clear NH3? Why does it cause hepatic encephalopathy.
Clears NH3 via the Glutamate–Glutamine cycle. When NH3 levels get high enough the brain pushes glutamate to glutamine. This effectively robs the neurons of neurotransmission ability.
Presentation/Enzyme def of:
McCardles
Cori
Pompe
von Gierke’s
McCardles (5): x Muscle Glycogen phosphorylase. Weakness and fatigue with exercise with little to no rise in blood lactate levels during exercise.
Cori (3): Debranching enzyme (1,6) def= Ketoacidosis, Hypoglycemia, hypertriglyceridemia, and hepatosplenomegaly. INCREASE IN HEPATOCYTE DEXTRINS (and no fatty inflitrate in liver)
Pompe (2) : x Acid Maltase (1,4). Pompe’s trashes the pump (cardiomegaly), lysosomal glycogen accumulation
von Gerke’s: (1) Glycogen phosphyrolase def=hepatomeagly, fasting hypoglycemia, lactic acidosis, hyperuricemia, hyperlipidemia
1) Lead poisoning inhibits what? Sxs?
2) AIP enzyme deficient? Sxs?
3) PCT enzyme deficient? Sx?
4) Rate limiting step? Cofactor?
5) Heme has negative feedback on what?
6) What stimulates Heme production?
1) ALAD (**Lea**D), Ferrochelatase. Microcytic anemia (sideroblastic anemia), GI and renal issues. Mental issues.
2) Porphobilinogen deaminase. Port wine colored urine, painful abdomen, polyneuropathy, psychological disturbances, precipitated by drugs*****
3) Uroporphyrinogen decarboxylase: blistering cutaneous photosensitivity (cuz the heme ring is formed and can absorbed radiation), most common. (“bURns when URoporphyringoen is bad)
4) ALAS (B6 factor)
5) ALAS
6) ETOH, Barbituates, Hypoxia
What vitamin can be given to rescue megaloblastic anemia in folate deprivation?
THYMIDINE (allowing for the salvage pathway to make dTMP)
Riboflavin Def causes the inhibition of what enzyme?
Succinate Dehydrogenase
“suck with lips which is where you get chelosis from riboflavin def”
Glucocorticoid’s affect on biochem energy pathways in the liver?
Muscle?
Potent stimulator of Gluconeogenesis and Glycogenesis (these normally don’t go together)
Catabolism in muscle
Hypoglycemia with prolonged fasting (1+ day) what enzyme defective?
Acetyl CoA Decarboxylase (cannot metabolize medium chain fatty acids)
OTC def vs Orotic Aciduria?
OTC def: HYPERAMMONIA
Orotic Aciduria: Refractory Megaloblastic anemia (x UMPS, Orotate phosphribyltransferase, oritidine 5’ transferase
What is the sequence upon which an AA is placed on a tRNA?
CCA with an OH- group at the end, on 3’ end
16s subunit of 30s ribo in pro’s is used for?
Contains nucleotide sequence to match complimentary mRNA sequence
Tyrosine growth factor receptor pathway?
Dimerization causes GDP to be exchanged for GTP which activates second messenger (eg RAS)
Tx for Homocysteinuria?
Tx for Orotic Aciduria
Pyridoxine
Uridine
