Biochem Flashcards
tetrahydrobiopterin
used as cofactor in synthesis of tyrosine (phe–>tyr), dopamine (Tyr–>dopa), serotonin (tryptophan–>serotonin), and nitric acid
via dihydrobiopterin reductase
(def an uncommon cause of PKU)
Cystic fibrosis
deletion of PHE at position 508 of CFTR gene
leading to defective protein-therefore less Cl transmembrane Cl channels
MSH2 MLH1
Code for MUT L and Mut S
Mistmatch repair gene mutations
account for >90% Lynch (HNPCC) genetic defects
sorbitol dehygrogenase
converts sorbital (made via glucose and aldose reductase) to fructose,
deficient in schwann cells, retinal and renal papilla leading to an accumulation in of sorbital
in lens the forward reaction has much less favorable kinetics and therefore can only keep up when small amounts of glucose are being converted to sorbitol
in states of hyperglycemia sorbital accumulates and cause deposits on lens and cataract formation
AAs on T arm of tRNA
thymine, cytosine, pseudouracil
sickle cell anemia gene defect
pt mutation in the 6th codon of the beta gene leading to valine (hydropobic) substitute for glutamic acid (hydrophilic)
-allowing for hydrophobic interactions and causing hb to aggregate in anaerobic conditions (more specifically bulging in beta chain fits in alpha chain hydrophobic region)
aldolase B def
fructose intolerance
metabolizes fructose 1 p to DHAP and glycerol–prevents glycogenolysis and gluconeogenesis
avoid fructose and sucrose (glucose+fructose)
mitochondrial metabolic pathways
beta oxidation of fatty acids, ketogenesis, TCA cycle, parts of urea cycle, pyruvate carboxylation
AA deriv of NO
arginine
AA deriv of urea
arginine and aspartate
AA deriv of Heme
glycine and succinyl CoA
AA deriv of creatinine
Glycine + arginine + SAM
AA deriv of GABA
glutamate
AA deriv of glutathione
Glutamate
AA deriv of pyrimidines
Glutamate + Aspartate
AA deriv of purines
Glutamate + Aspartate + Glycine
AA deriv of histamine
histidine
AA deriv of dopamine
Phe–>tyrosine–>Dopa–>dopamine
AA deriv of melatonin
Tryptophan–>serotonin–>melatonin
AA deriv of niacin
tryptophan
AA deriv of Melanin
Tyrosine
alpha galactosidase A def
Fabrys disease
accumulation of ceramide trihexoside
ancoparesthesias, angiokeratomas, heart/renal disease
DNA methylation at CpG islands
represses transcription
histone methylation
reversible represses DNA transcription
histone acetylation
relaxes DNA coiling and allows for transcription
GAG AAs
necessary for purine synthesis
Glutamine
Aspartate
Glycine
orotic acidura
defect in pyrimidine production -hypochromic megaloblastic anemia growth retardation excretion of high amounts of orotic acid in the urine
methotrexate/trimethoprime.pyrimethamine
all inhibit dihydrofolate reductase
adenosine deaminase deficiency
major cause of SCID
necessary for purine metabolism
leads to accumulation of adenosine which is toxic to lymphocytes
prevents DNA synthesis
Lesch Nyhan syndrome
defective absent HGPRT (hypoxanthine guanin phosphoribosyltransferase)
which converts gunaine to GMP and hypothanxine to IMP
excess uric acid production and de novo purine synthesis
-HGPRT
hyperuricemia
Gout
Pissed off (self mutilation, aggression)
Retardation
dysTonia
treatment: allopurinal or febuxostat (2nd line)
allopurinol/febuxostat
blocks conversion of hypoxanthine to xanthine and xanthine to uric acid
fluoroquinolones mech
inhibit topoisomerase II and IV
DNA pol III
5’-3’ synthesis, 3’-5’ exonuclease
DNA pol I
prok only
same as DNA pol III but can excise RNA primer
sickle cell dz mutation
missense substitution of glutamic acid with valine
duchenne muscular dystrophy mutation
frameshift-resulting in truncated nonfuncitonal dystrophin protein
DNA repair of bulky helix distorting lesions
nucleotide excision repair
defective in xeroderma pigmentosa
-cannot fix thymine dimer induced by UV light
-increase aging, skin cancer (squamous cell carcinoma and malignant melanoma)
in G1 phase
DNA repair of single NT mistakes
Base excision repair
- glycosylase removes bad base creating an AP (apurinic/apyrimidic) site
- endonuclease cleaves 5’ site
- lyase cleaves 3’ site
- DNA pol fills in, ligase seals
mismatch nucleotides
-repair of newly synthesized strand MUT S detects mismatch and recruits MUT L-exonucelase removes mismatch and DNA pol fills -defective in HNPCC in G2 phase -
DNA repair of double stranded breaks
nonhomologous end joining
- 2 ends of DNA are brought together, may lose some DNA
- defective in ataxia telangiectasia and Fanconi anemia
- hypersensitive to ionizing radiation
ataxia telangiectasia
defective nonhomoloug DsDNA repair
-get cerebellar atrophy and repeated sino/pulmonary infections
-
amantia phalloides
mushroom cap
causes severe hepatotoxicity
-inhibits RNA pol II (makes mRNA)–[Pol I makes rRNA and III makes tRNA) -none have proofreading funciton
rifampin
inhibits RNA pol in prokaryotes
actinomycin D
inhibits RNA pol in euk and prok
p bodies
mRNA quality control, contain exonucleases, decapping enzymes and microRNAs -mRNA may be stored in P bodies and not used till much later
anti smith antibodies
highly specific for SLE
antibodies against snRNPs (part of splicesome that take introns out of mRNA)
thymine pseudourasil cytosine
T arm of tRNA
necessary sequence for binding with ribosome
D arm of tRNA
contains dihydrouracil necessary for tRNA recognition by correct amino-acyl tRNA synthetase
Li Fraumeni syndrome
have defect in p53, Rb tumor suppresors which normally regulate G1–>S phase progression
SER high in
liver, steroid hormone producing cells of adrenal cortex and gonads
mannose 6 phosphate signal
added by golgi-signals protein to lysosome
golgi modifications on proteins
modifies N-oligosaccharides on asparagine and adds O-oligosachhardises on serine and threonine
coarse facial features, clouded cornea, restricted joint movement,
- high lysosomal plasma levels
I cell disease
-defective N acetylglucosaminyl-1 phosphotransferase that leads to inability of golgi to add mannose signal to proteins
(usually fatal in childhood)
COPI
COPII
Clarthrin
COPI: retrograde–golgi trans–cis–ER
COPII: anterograde-ER–Cis–trans
Clathrin: endosomes -receptor mediated endocytosis-LDL receptor activity
dyenin
microtubule associated carrier protein
works in retrograde fashion from + to - mt end
kinesin
microtubule associated carrier protein, works in anterograde fashion from - to + ends
int filaments staining Vimentin Desmin cytokeratin GFAP Neurofilaments
vimentin-connective tissues desmin-muscle cytokeratin-epithelial tissues GFAP-neuroglia neurofilments-neurons
kartagener syndrome
primary ciliary dyskinesia
- immotile cilia due to dyenin arm defect
- infertile-no motile sperm and fallopian tube defect, bronchiectasis, recurrent sinusitis, situs inversus
digoxin/digitoxin
directly inhibit Na/K ATPase which indirectly inhibts Na/Ca exchange, making the cytoplasm have a high Ca content, increasing contractility
collagen type I
bone, skin, tendon, cornea
-defective in OI
collagen type II
cartilage
collagen type III
reticulin-blood vessels, uterus, fetal tissues, granulation tissue
-defect rare-vascular type of Ehler Danlos syndrome
collagen type IV
basement membrane, lens, basal lamina
-defective in alport syndrome, auto-antibodies directed against it in good pasture syndrome
best reflection of collagen synthesis
glycine-every 3rd residue
which step of collagen synthesis requires vitamin C?
hydroxylation of proline/lysine residues
menkes
defective collagen cross linking (lysine to hydroxy lysine) due to mt menkes protein leading to decreased copper absorption and therefore decreased activity of lysyl oxidase (needs copper)
-brittle, kinky hair, growth retardation, hypotonia
aging wrinkles
decreased collagen and elas tin FORMATION
FAVA beans
can precipitate hemolytic anemia in patients with glucose 6 dehydrogenase def. (used in HMP shunt) and therefore do not produce adequate NADPH necessary for RBS protection against ROS (used in reducing glutathione)
amyl nitrate
converts hemoglobin into methhemoglobin whic has low affinity for oxygen but high affinity for CN and shunts this away form organelles (mitochondria) where it would induce damage
pyruvate kinase deficiency
necessary for the conversion of phosphoenolpyruvate to pyruvate, producing ATP
-without it RBCs are hemolyzed bc of the insufficinect amount of ATP generated to maintain RBC cellular structure
measles supplementation
vitamin A
alkaptonuria
defective homogestisic acid oxidase-blocking tyrosine metabolism to fumarate, get accumulation of homogentistic acid which selectively accumulates in cartilage of ear, nose and turns black, also turns urine black
excessive egg white ingestion
leads to biotin deficiencey (avindin found in egg whites binds biotin making it inactive)
-biotin is necessary for the conversion of pyruvate to oxaloacetate in gluconeogeneiss)
burning feet syndrome
pantothenic acid deficiency (coenzyme A/vitamin B5)
-impt in the TCA cycle binds with oxaloacetate to form citrate
-also necessary for the production of Vitamin A, D, cholesterol, steroids, heme A, fatty acids, AAs, and proteins
causes feeet dysesthesias, paresthesias, edmea of lower extremities, chronic diarrhea, greasy stool
thiamine participates as a cofactor in which glucose metabolic pathways
- part of pyruvate dehrogenase which converts pyruvate to acetyl coa
- with alpha ketoglutarate dehydrogenase in the TCA cycle
- HMP shunt with transketolase converting ribulose 5-p to G3P, F6P, and ribose5P
high intracellular NADH in the setting of hypoglycemia
indicative of alcohol ingestion-alcohol serves as a form of energy and through its metabolism creates NADH, high NADH then shunts pyruvate from TCA to lactate
cafe au lait spots, polyostotic fibrous dysplasia, percocious puberty, many endocrine abnormalities
McCune Albright Syndrome
- due to defect in G protein signaling, example of mosaicism,
- lethal if mutation occurs before fertilization
prader willi
imprinting of maternal gene. chromosome 15, paternal gene then deleted, results in hyperphagia, small gonads, obesity, intellectual disability, hypotonia
angelman
imprinting of paternal gene with subsequent maternal gene deleted/mutated, results in inappropriate laughter, seizures, ataxia, severe intellectual disability,
autosomal dominant diseases
ADPCKD-PKD1 gene chr 16 FAP-APC gene chr 5 Familial hypercholesterolemia hereditary hemorrhagic telangiectasia Hereditary shpherocytosis: defect in spectrin or ankyrn Huntingtons disease CAG repeat chr 4 Li fraumeni syndrome: abnml Tp53 gene--many malignancies at a very young age Marfan: defective fibrin gene FBN1 chr 13 MEN associated with RET gene Myotonic dystrophy NF1: NF1 ch 17 NF2: NF2 ch 22 tuberous sclerosis: VHL: deletion of VHL chr 3
autosomal recessive diesases
CF, sickle cell anemia, ARpkd, glycogen storage disorderd, kartagener syndrome, mucopolysaccharidoses (except hunter), PKU, sphingolipidoses (except Fabrys) Thalassemia, Wilsons
X linked recessive diseases
Be Wise, Fool's GOLD Heeds SIlly Hope Bruton agammaglobulinemia Wiskott Aldrich syndrome, Fabry, G6PD, Ocular albinism, Lesh Nyhan, Hunter SYndrome, Hemophilia A and B, Ornithine transcarbamylase A and B
myotonic dystrophy type 1
My tonia, my testicles, my toupee, my ticker
CTG trinucleotide repeat of DMPK gene
fragile X syndrome
CGG nucleotide repeat of FMR1 gene
-MR, macroorchidism, joint laxity, pes cavus, MVP, long face with large jaw
Trinucleotide expansion diseases
Huntinton (CAG) myotonic dystrophy (CTG) fragile X (CGG) friedrich ataxia (GAA)
decreased PAPPA
increased b HCG
increased nuchal translucency
downs syndrome findings in first trimester
Decreased estriol
decreased alpha fetoprotein
increased b HCG
increased inhibin A
downs syndrome findigns in second trimester
rocker bottom feet, micrognathia, low seat ears, clenching hands,
Edwards syndrome trisomy 18, most die after 1 year
decreased PAPPA
decreased b HCG
edwards syndrome (trisomy 18)
decrased alpha fetoprotein
decreased bHCG
decreased estriol
decreased PAPPA
edwards, trisomy 18
cleft lip/palate, holoprosencephaly, polydacytly, congenital heart disease, rocker bottom feet, micropthamnia
Patau trisomy 13
decreased b HCG
decreased PAPPA
increased fetal nuchal translucency
Patau syndrome trisomy 13
cardiac abnormalities, epicanthal folds, microcephaly, intellectual disability, mewing sound
cri du chat, congenital deletion of short arm of chromosome 5
elfin faces, intellectual disability, hypercalcemia (increased sensitivity to Vitamin D) well developed verbal skills, extreme friendliness to strangers, cardiovascular problems
williams syndrome
congenital microdeletion of long arm of chromosome 7
CATCH22
microdeletion at chromosome 22q11 C: cleft palate A: abnormal facies T: thymic aplasia C: cardiac defects H: hypocalcemia 2/2 parathyroid aplasia DiGeorge: thymic, parathyroid and cardiac defects Velocardiofacial syndrome: palate, facial, and cardiac defects
dry scaly skin, night blindness, immunosuppresion, corneal degeneration, bitot spots on conjunctiva
Vitamin A deficiency
vitamin A excess
acute: N/V, blurred vision
Chronic: alopecia, dry skin, pseudotumor cerebri, arthralgias
teratogenic: cleft palate, cardiac abnormalities,
high output cardiac failure and LE edema
wet BerIBerI
vitamine B1 def
polyneuritis, symmetrical muscle wasting
dry BerIBerI
vitamin B1 def
increase in RBS transketolase activity following infusion of thiamine
diagnosis for B1 defiency (wenicke korsakoff/beriberi)
cheiliosis and corneal vascularization
vitamin B2 def
riboflavin
necessary for FAD.FMN
B2=2ATP
synthesis reactions requiring B6
- cystathione
- heme
- niacin
- histamine
- serotonin
- NE
- epi
- DOPA
- GABA
reactions which require Biotin
Vit B7
carboxylation reactions
-pyruvate carboxylase (pyruvate–>oxaloacetate)
-Propionyl carboxylase (propionyl CoA–>methylmalonyl CoA)
-AcetylCoA carboxylase (Acetyl Coa–>Malonyl CoA)
causes of B12 deficiency
colbalamin
(have pool stores for years in the liver)
-insufficient intake (veganism)
-malabsorption (celiac sprue, enteritis, Diphyllobothrium latum)
-lack of intrinsic factor (pernicious anemia, gastric bypass)
-absence of terminal ileum (Crohn disease)
function of Vitamin C (pathways)
hydroxylation of proline and lysine in collagen synthesis, dopamine Beta hydroxylase (converts dopamine to NE), facilitates absorption of iron by reducing to the Fe2+ ferric state
corskcre hair, easy bruising, sollen gums, petechiae, hemarthrosis, anemia, poor wound healing
SCURVY
ancillary treatment for methemoglobinemia
vitamin C
-reduces Fe3+ to Fe2+
hemolytic anemia, acanthocytosis, posterior column and spinocerebellar tracy demyelination
Vitamin E deficiency
-like B12 without megaloblastic anemia or hypersegmented neutrophils or increased serum MMA
dealyed wound healing, altered sense of tase/smell (dysgeusia/anosmia), acrodermatitis enteropathica
Zinc def
-may predispose to alcoholic cirrhosis
Kwashiorkor
MEAL malnutrition edema anemia liver (fatty)
Marasmus
calorie malnutrition resulting in muscle wasting, edema loss of sub q fat
ATP production from glycolysis with arsenic poisoning
ZERO ATP
reactions involving Vitamin b6
transamination (an alpha keto acid joins with an AA to bceome an AA)
and in decarboxylation reactions
tender loving care for nancy
cofactors required by branched chain alpha dehydrgoenase, pruvate dehydrogenase and alpha keoglutarate dehydrognease Thiamine Lipoate CoA FAD NAD
vomiting, rice water stools, garlic breath
arsenic poisoning–>inhibits lipoic acid (a key component of pyruvate dehydrogenase complex)
high orotic acid in blood, urine, decreased BUN, tremor, slurred speech, somnolence, vomiting, cerebral edema, blurred vision
high ammonia secondary to ornithine transcarbamylase deficiency
-difference between this and orotic aciduria is no megaloblastic anemia is seen here
hereditary dysfunction of PCT preventing absorption of COLA
cystinuria -cystine -ornithine -lysine -arginine AT urinary cyanide-nitroprusside test is diagnostic -causes hexagonal stone to precipitate tx: urinary alkalinization (potassium citrate, acetazolamide) and chletating agents (penicillamine)
intellectual disability, marfanoid, osteoporosis, lens subluxation, kyphosis, thrombosis, atherosclerosis
homocytinuria
- due to def in cystathionine synthase
treatment: decreased methionin, increase cysteine, increase b12/folate in diet
dark connective tissue, brown pigmented sclera, urine turns black on prolonged exposure to air
alkaptonuria
-due to def in homogentisate oxidase
can have debilitating arthralgias -homogentisic acid is toxic to cartilage
lactulose give with…
binds ammonia, acidifies GI tract
- given with rifaxamin to decrease colonic ammoniagenic bacteria
- benzoate or phenylbutyrate decrease ammonia by binding and causing its excretion
developmental delay, corneal clouding, gargoylism, airway obstruction
hunters
deficiency of alpha L iduronidase
get accumulation of heparan suflate dermatan sulfate
developmental delay, gargoylism, aggressive behavior, airway obstruction
hurlers
-iduronate sulfatase deficiency
get buildup of dermatan and hapran sulfate
central and peripheral ataxia with dementia, buildup of cerebroside sulfate
Metachromic leukodystrophy
-def of arylsulfatase A
globoid cells, peripheral neruopathy,d evelopmental delya, optic atrophy
Krabbe disease
buildup of galactocerebroside/psychosine due to def of galactocerebrosidase
cherry red spot, no HSM, progressive neurodegeneration, developmental delay, lysosomes with onion skin
tay sachs def of hexosaminosidase A
cherry red spot, Hsm, developmental regression, fomay histocytes,
neiman picck def of sphingomyelinase get accumulation of sphingomyelin
pancytopenia, HSM, asecptic necrosis of femur, bone crisis, osteoporosis, lipid laden macrophages that look like crinkled tissue paper
gauchers disease
-def of glucocerebrosidase with accumulation of glucocerebroside
acroparesthesia, angiokeratomas, cardiovascular/renal
Fabrys def of alpha galactosidase A with accumulation of ceramide trihexose
hypoketotic hypoglycemia with vomiting, lethargy, seizures, liver dysfunciton
def of medium chain acyl COA dehydrogenase -disorder of fatty acid oxidation and therefore breakdown to acetyl coa
systemic primary carnitine def
cant transport long chain fatty acids into the mitochonria
-toxic accumulation causing weakness, hypotonia and hypoketotic hypoglycemia
