FA Biochem II Flashcards
what is dominant negative mutation and give an example
exerts a dominant effect, a heterozygote produces a nonfxnal altered protein that also prevents the normal gene from functioning, mutation of Tx factor its allosteric site, nonfxning mutant can still bind DNA, preventing wild type Tx from binding
What is linkage disequilibrium
tendency for certain alleles at 2 linked loci to occur together more often than expected by chance - varies is different populations
What is mosaicism and give an example
occurs when cells in the body have different genetic makeup, can be germline mosaic, which may produce a disease that is not carried by parents somatic cells - lyonization-random X inactivation in females
What is locus heterogeneity and give an example
mutations at different loci can produce the same phenotype, marfans, MEN 2B, homocystinuria; all cause marfinoid habitus, also albinism
What is heteroplasmy
presence of both nl and mutated mtDNA resulting in mitochondrial inherited disease
What is uniparental disomy
offspring receives 2 copies of a chromosome from 1 parent and no copies from the other parent
What is the Hardy Weinberg disease prevalence equation
p2 +2pq+ q2 = 1
What is the hardy weinberg allele prevalence
p+q = 1
What is the hardy weinber heterozygote prevalence
2pq
What is the prevalence of an X-linked recessive disease in males and in females
q, q2
What are the 4 assumption of the Hardy Weinberg law
no mutation occuring at the locus, no selection for any genotypes at the locus, completely random mating, no migration
Gene imprinting implies that how many alleles are active at a single locus
one
If two alleles are present, but the active allele is deleted, what happens
disease
What are the characteristics of prader willi syndrome how does it occur
mental retardation, hyperphagia, obesity, hypogonadism, hypotonia - deletion of normally active paternal allele on chromosome 15
What are the characteristics of angelmans syndrome and how does it occur
mental retardation, seizures, ataxia, inappropriate laughter - deletion of normally active maternal allele
characterize autosomal domint inheritance
many generations, both male and female affected - often pleiotropic, can present clinically after puberty
characterize autosomal recessive inheritance
1/4 of offspring from 2 carrier parents are affected, often enzyme def, usually only seen in 1 generation - often more sever than AD, presents in childhood
characterize x linked recessive
sons of heterozygous mothers have 1/2 half chance of being affected - no male to male transmission, and often more severe in males, heterozygous females may be affected
characterize x linked dominant
transmitted through both parents, affected mother may have affected children, affected father will have affected children
What bone disorder has x linked dominant inheritance
hypophophatemia rickets - vit D resistant ricketts, inc wasting of phosphate in proximal tubule, rickets like presentation
characterize mitochondrial inheritance
transmitted only through mother, all offspring of affected females may show signs of disease
Give an example of a mitochondrial inherited disease
lebers hereditary optic neuropathy - degeneration of retinal ganglion cells and axons - leads to acute loss of central vision. Mitochondrial myopathies
cell signaling defect of fibroblast growth factor (FGF) receptor 3, results in dwarfism, short limbs, head/trunk nl size, associated with advanced paternal age
achondroplasia
bilateral, massive enlargement of of kidneys due to multiple large cysts
ADPKD
How does patients present with ADPKD
flank pain, hematuria, HTN, progressive renal failure
90% of ADPKD cases are due to a mutation in what gene
APKD1 on chromosome 16
ADPKD is associated with what additional conditions
polycystic liver disease, berry aneurysm, mitral valve prolapse
colon becomes covered witih adenomatous polyps after puberty, progresses to colon cancer unless resected
FAP
FAP is due to deletion on what gene on what chromosome
APC on chromosome 5
elevated LDL due to defective or absent LDL receptor - heterozygotes have cholesterol ~300, homozygotes ~700
familial hypercholesterolemia, hyperlipidemia type IIA
What are the complications/signs of familial hypercholesterolemia
sever atherosclerotic disease early in life, and tendon xanthomas on the achilles, MI may develop before 20
telangiectasia, recrrent epistaxis, skin discolorations, AVMs
hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome)
spheroid RBCs due to spectrin or ankyrin defect, hemolytic anemia, inc MHCH, splenectomy is curative
hereditary spherocytosis
depression, progressive dementia, choreiform movements, caudate atrophy and dec levels of GABA and ACH in the brain
Huntingtons
What trinucleotide repeat in Huntingtons and what chromosome is it found on
CAG, 4
fibrillin defect leading to connective tissue disorder affecting skeleton, heart, and eyes
marfans
what findings are associated with marfans
tall with long extremeties, pectus excavatum, hyperextensive joints, arachnodactyly
Describe the pathophys of the aorta in a pt with marfans, and the eyes
cystic medial necrosis of aorta leading to aortic incompetence and dissecting aortic aneurysms, floppy mitral valve, subluxation of lenses
several distinct syndromes characterized by familial tumors of endocrine glands including pancreas, parathyroid, pituitary, thryoid and adrenal medulla - disorders and gene association
MEN - 2A and 2B with ret gene
café au lait spots, neural tumors, lisch nodules, skeletal disorders, optic pathway gliomas
neurofibromatosis type 1 (von Recklinghausens disease)
What chromosome is the NF gene on
17, 17 letters in von Recklinghausen
bilateral acoustic schwannomas, juvenile cataracts
NF2 on chromosome 22
facial lesions, hypopigmented “ash leaf spots,” cortical and retinal hamartomas, seizures, mental retardation, renal cysts, renal angiomyolipomas, cardiac rhabdomyomas, inc risk of astrocytomas
tuberous sclerosis
deletion of VHL gene on chromosome 3 leading to hemangioblastomas of retina/cerebellum/medulla bilateral RCC - dz and overexpression product
von hippel lindau, 3
What do albinism, ARPKD, CF, glycogen storage diseases, hemochromatosis, mucopolysaccharidoses (except Hunters) PKU, sickle cell, sphingolipodoses (except Fabrys) thalassemias have in common
autosomal recessive diseases
CF, is AR deletion in what gene on what chromosome resulting in a deletion inf what
CFTR gene, 7, Phe 508
What does the CFTR channel do in the lungs, GI tract and skin
active secretion in lungs and GI, reabsorbs in skin
What does a defective Cl channel do
secretion of abnl thick mucus that plugs lungs, pancreas, liver
recurrent pulmonary infxns in CF are due to what organisms
pseudomonas and s aureus
What are the results of pancreatic insuff in CF
malabsorption and steatorrhea (ADEK)
What are the results of CF on male fertility
males are infertile due to bilateral absence of vas deferens
How do you diagnose CFTR
inc Cl- in sweat
What does the mutation in the gene cause in protein synthesis
abnormal protein folding, degradation before reaching cell surface
What is the TX for CF and what does it do
N-acteylcysteine, cleave disulfide bonds within mucus glycoproteins
Name as many x-linked recessive disorders as you can
bruton’s agammaglobulinemia, wiskott-aldrich, fabrys disease, G6PD def, ocular albinism, Lesch-Nyhan syndrome, Duchenne and Becker Muscular Dystrophy, hunter’s syndrome, hemophilia A and B
What leads to the deletion of the dystrophin gene in duchenne’s muscular dystrophy
x linked frame shif mutation
what does the deletion of the dystrophin gene lead to
accelearted muscle breakdown
What is pseudohypertrophy in the calf a result of, and what are the cardiac manifestations
fibrofatty replacement of muscle, cardiac myopathy
What is Gowers maneuver
assistance of upper extremities to stand up
What is the mutation in beckers muscular dystrophy, what is the severity and time of onset
mutated dystrophin gene, less severe, adolescence
What is the physiologic role of dystrophin
anchor muscle fibers, primarily in skeletal and cardiac muscle
What is used to diagnose muscular dystrophies
inc CPK and muscle biopsy
what gene is implicated in fragile X syndrome, and what is the mutation
FMR1 gene, methylation, associated with chromosomal breakage
What are the physical findings of fragile x syndrome
mental retardation, macro-orchidism, long face with large jaw, large everted ears, autism, and mitral valve prolapse
What is the trinucleotide repeat in fragile X
CGG
trinucleotide repeat for huntingtons
CAG
trinucleotide repeat fo myotonic dystrophy
CTG
nucleotide repeat for fragile x
CGG
nucleotide repeat for fredreich’s ataxia
GAA
What are the findings in Down’s syndrome
mental retardation, flat facies, prominent epicanthal folds, simian crease, gap between 1st 2 toes, duodenal atresia, congenital heart disease (ASD), inc risk of ALL and Alzheimers
What causes Down syndrome
meiotic nondisjunction of homologous chromosomes (associated with advanced maternal age) leading to trisomy 21
A small proportion of Down syndrome is due to what two genetic events
robertsonian translocation and mosaicism
What are the fetal screening measures for Down
dec AFP, inc betahCGH, dec estradiol, inc inhibin - inc nuchal translucency on US
What causes Edwards syndrome and what is it
trisomy 18, severe mental retardation, rocker bottom feet, micrognathia, low set ears, clenched hands, prominent occiput, congenital heart disease, death usually within the first year
What causes patau’s syndrome and what is it
trisomy 13, severe mental retardation, rocker bottom feet, micophthlamia, microcephaly, cleft lip/palate, holoprosencephaly, polydactyly, congenital heart disease, death usually within the first year
Describe robertsonian translocation
nonreciprocal chromosomal translocation that commonly involves chromosome pairs 13, 14, 15, 21, 22
Do balanced translocations cause abnl phenotype
no
What are the results of unbalanced translocation
miscarriage, stillbirth, chromosomal imbalance (down, patau)
congenital microdeletion of short arm of chromosome 5 with microcephaly, moderate to severe mental retardation, high pitched crying/meying, epicanthal folds, cardiac abnl
cri du chat
congenital microdeletion of long arm of chromosoe 7 with findings of elfin facies, mental retardation, hypercalcemia, well developed verbal skills, extreme friendliness with strangers, cardiovascular problems
williams syndrome
What does CATCH 22 stand for and what causes is
aberrant 3rd and 4th branchial arches causing 22q11 deletion - cleft palate, abnl facies, thymic dysplasia, cardiac defects, hypocalcemia secondary to parathyroid aplasia
What defects characterize DiGeorge syndrome
thymic, parathyroid and cardiac
What defects characterize velocardiofacial syndrome
palate, facial and cardiac defects
What are the fat soluble vitamins and what does their absorption depend on
ADEK, dependent on gut (ileum) and pancreas -accumulate in fat and can cause toxicity
Broadly, what can cause fat-soluble vitamin deficiencies
malapsorption syndromes like sprue or CF or mineral oil intake
What are the water soluble vitamins, which ones are stored
B(1, 2, 3, 5, 6, 12) C, biotin and folate (B12 and folate are stored)
What do B-complex vitamin deficiencies often result in
dermatitis, glossitis, and diarrhea
What are the functinos of vitamin A
antioxidant, constituent of visual pigment, essential for nl differntiation of epithelial cells into specialized tissue (pancreatic cells, mucus secreting cells) used to treat measles
What are the symptoms of vit A def
night blindness, dry skin
What are the symptoms of vit A excess
athralgias, fatigue, headaches, skin changes, sore throat, alopecia
What are the teratogenic effects of vit A and what test must be ordered before starting a woman on isotreitinoin for severe acne
cleft palate, cardiac abnl, pregs test
What is Retin A used topically for
wrinkles and acne
Where is vit A found in the diet
liver and leafy veggies
What is the name and function of vit B1
thiamine, in thiamine pyrophosphate a cofactor for pyruvate dehydrogenase (glycolysis), alpha ketoglutarate dehydrogenase (TCA cycle), transketolase (HMP shunt), and branched-chain AA dehydrogenase
What is the results of vit B1 def
impaired glucose breakdown leading to ATP depletion; highly affected aerobic tissues like brain and heart affected first
What 3 syndromes are associated with vit B1 def
wernicke-korsakoff, dry and wet beriberi
What is the wernicke-korsakoff clinical picture
confusion, opthalmoplegia, ataxia, confabulation, personality changes and memory loss
What neuroanatomical strutures are injured in wernicke-korsakoff
medial dorsal nucleus of thalamus, mamillary bodies
What happens with dry beriberi
polyneuritis, symmetrical muscle wasting
What happens with wet beriberi
high output cardiac failure, dilated cardiomyopathy, edema
What is the name and function of vit B2
riboflavin, cofactor in oxidation and reduction (FAD and FMN are derived from riboflavin)
What happens in vit B2 def
cheilosis - inflammation of lips, scaling and fissures at the corner of the mouth, corneal vascularization
What is the name is fxn of vit B3
niacin, constituent of NAD and NADP, derived from tryptophan
Synthesis of vit B3 requires what other vitamin
B6
What does vit B3 def result in
glossitis - severe = pellagra - diarrhea, dermatitis, dementia
what disease can cause pellagra
hartnup disease - dec tryptophan absoprtion, malignant carcinoid syndrome (inc tryptopha metabolism) and INH (dec vit B6)
What can excess vit B3 cause
facial flushing
What can vit B3 be used to treat
hyperlipidemia
What is the name and fxn of vit B5
pantothenate, essential component of CoA, a cofactor for acyl transfers and fatty acid synthase
What is the result of vit B5 def
dermatitis, enteritis, alopecia, adrenal insuff
What is the function and name of vit B6
pyroxidine, converted to pyroxidine phosphate a cofactor used in transamination, decarboxylation, glycogen phosphorylase, cystathionine synthesis and heme synthesis - required for synthesis of niacin and tryptophan
What is the result of vit B5 def
convulsions, hyperirritability, peripheral neuropathy, deficiency inducible by INH and oral contraceptives, sideroblastic anemais
What is the name and fxn of vit B12
cobalamin - cofactor of homocysteine and methyltransferase, methylmalonyl CoA mutase
Where is vit B12 found
animal products, synthesized only by microorganisms, large reserve pool, mainly in liver
What happens in a B12 def
macrocytic, megaloblastic anemia, hypersegmented PMNs, neurologic symptoms, (parasthesias, subacute combined degeneration) due to abnl myelin, prolonged becomes irreversible
What causes B12 def
malabsorption (sprue, enteritis) lack of intrinsic factor from pernicious anemia, gastric bypass surgery or absence of terminal ileum as in Crohns
Infection with what organism can cause B12 def
diphyllobothrium latum
What test is used for B12 def
Schilling test
What is the function of folic acid
converted to THF, a coenzyme for one-carbon transfer/methylation reactions, important for synthesis of nitrogenous bases in DNA and RNA
What is the main source of folate
foliage, small reserve in liver, eat green leaves
What happens in folate def
macrocytic, megaloblastic anemia, no neurologic sx, most common vit def in the US, seen in EtOH and pregs
What drugs can cause folate def
phenytoin, MTX, and sulfonamides
Giving folate during early pregnancy is important to prevent what birth defects
neural tube
What components come together to make S-adenosyl methionine
ATP and methionine
What does SAM do
transfers methyl units
What is regeneration of methionine depedent on
B12 and folate
What catacholamine step is SAM required for
conversion of NE to epi
What is the function of biotin
cofactor of carboxyltion enzymes: pyruvate carboxylase, acetate-CoA carboxylase, and propionyl-CoA carboxylase
What substance in egg whites binds biotin
Avidin
pyruvate carboxylase catalyzes what rxn
pyruvate to oxaloacetate (3C to 4C)
Acetyl-CoA carboxylase catalyzes what rxn
acetyl-CoA to malonyl-CoA (2C to 3C)
What rxn does propionyl-CoA carboxylase catalyze
propionyl-CoA to methylmalonyl-CoA (3C to 4C)
What does biotin def cause
dermatitis, alopecia, enteritis
What causes biotin def
antibiotic use or excessive ingestion of raw eggs
What are the names and sources of the two types of vit D found in nature
D2 = ergocalciferol -ingested from plants D3 = cholecalciferol - ingested from milk, formed in sun exposed skin
How is vit D stored
25OHD3
What is the active form of vit D
1,25 OH2 D3 = calcitriol
What is the fxn of vit D
inc intestinal absorption fo calcium and phosphate, inc bone resorption
What happens in vit D def
rickets in kids -bending bones, osteomalacia in adults, hypocalcemia tetany, breast milk has dec vit D (supplement in dark skinned patients)
What happens in vit D excess
hypercalciuria, loss of appetite, stupor, seen in sarcoidosis from activation fo vit D by epithelioid macrophage
What are the function of vit C
antioxidant, facilitates iron absorption by keeping iron in the Fe2+ reduced state, necessary for hydroxylation of proline and lysine collagen bridges, necessary for dopamine beta hydroxylase which converts DA to NE
What does vit C def cause
scurvy - swollen gums, bruising, hemarthrosis, anemia, poor wound healing, weakened immune response
What is the fxn of vit E
antioxidant, protects RBCs and membrances from free radical damage
What does vit E def cause
inc fragility of RBC, hemolytic anemia, muscle weakness, posterior column and spinocerebellar tract demyelination
What is the fxn of vit K
gamma carboxylation of glutamic acid residues on various proteins concerned with blood clotting, synthesized in intestinal flora
What clotting factors require vit K
II, VII, IX, X (1972) protein C and S
What happens in vit K def
neonatal hemorrhage with inc PT and PTT, but nl bleeding time, can also occur after prolonged use of broad spectrum Abx
How does warfarin work
vit K antagonist
What is the function of Zinc
essential for the activity of over 100+ enzymes, important in the formatio of zinc fingers,
What happens in zinc def
delayed wound healing, hypogonadism, dec in adult hair, dysguesia, anosmia, may predispose to EtOH cirrhosis
What two enzymes are involved in EtOH metabolism
EtOH dehydrogenase and acetaldehyde dehydrogenase
Where is EtOH dehydrogenase located
cytosol
Where is acetaldehyde located
mitochondria
What is the limiting reagent in EtOH metabolism
NAD+
What order kinetics does EtOH dehydrogenase have
zero
what does fomepizole do
inhibits EtOH dehydrogenase and is an antidote for methanol and ethylene glycol poisoning
What is disulfiram used for
inhibits acetaldehyde dehydrogenase and contributes to hangover symptoms
how does ethanol induce hypoglycemia
inc NADH/NAD ratio in liver, causing diversion of pyruvate to lactate and OAA to malate, inhibiting gluconeogenesis and stimulating fatty acid synthesis. Leads to hypoglycemia and hepatic fatty liver change seen in chronic EtOH users
protein malnutrition resulting in skin lesions, edema and liver malfxn
kwashiorkor - small child with swollen belly
energy malnutrition resulting in tissues and muscle wasting, loss of subQ fat, variable edema
marasmus - muscle wasting
What metabolic rxns occur in the mitochondria
fatty acid oxidation, acetyl-Coa production, TCA cycle, OXPHOS
What metabolic rxns occur in the cytoplasm
glycolysis, fatty acid synthesis, HMP shunt, protein synthesis (RER), steroid synthesis (SER)
What metabolic rxns occur in both the cytoplasm and mitochondria
heme synthesis, urea cycle and gluconeogenesis - HUGs take two
what does a kinase do
uses ATP to add high energy phophate group onto substrate
What does a phosphorylase do
adds an inorganic phosphate onto substrate without using ATP
what does a phosphatase do
removes phosphate group from substrate
what does a dehydrogenase do
oxidizes substrate
what does a carboxylase do
adds 2 carbon with the help of biotin
What is the rate determining enzyme (RDE) of glycolysis
phosphofructokinase 1
What is the RDE of gluconeogenesis
fructose 1,6 bisphosphate
What is the RDE of TCA cycle
isocitrate dehydrogenase
What is the RDE of glycogen synthesis
glycogen synthase
What is the RDE of glycogenolysis
glycogen phosphorylase
What is the RDE of the HMP shunt
glucose 6 phosphate dehydrogenase (G6PD)
What is the RDE of de novo pyrimidine synthesis
carbomoyl phosphate synthetase II
What is the RDE of de novo purine synthesis
glutamine PRPP amidotransferase
What is the RDE of the urea cycle
carbomoyl phosphate synthetase I
What is the RDE of fatty acid synthesis
Acetyl-CoA carboxylase (ACC)
What is the RDE of fatty acid oxidation
carnitine acyltransferase I
What is the RDE of ketogenesis
HMG-CoA synthase
What is the RDE of cholesterol synthesis
HMG-CoA reductase
How many ATP are created by aerobic metabolism of glucose in the heart and liver via what shuttle
32, malate aspartate shuttle
How many ATP are created by aerobic metobolism of glucose in muslce via what shuttle
30, glycerol-3-phosphate shuttle
How many ATP are produced by anearobic glycolysis per molecule of glucose
two
How is ATP used by the cell
ATP hyrdolysis couple to energetically unfavorable rxns
What is the activated carrier for phosphoryl
ATP
What is the activated carrier for electrons
NADH, NADPH, FADH2
What is the activated carrier for Acyl
coenzyme A, lipoamide
What is the activated carrier for Co2
biotin
What is the activated carrier for 1 carbon units
THFs
What is the activated carrier for methyl groups
SAM
What is the activated carrier for aldehyddes
TTP
What is NAD+ generally used for
catabolic processes to carry reducing equivalents away as NADH
What is NADPH used for
anabolic processes as a supply of reducing equivalents
What produces NADPH
HMP shunt
NADPH are used in what 4 things
anabolic processes like steroid and fatty acid synthesis, respiratory burst, P-450, glutathione reductase
phosphorylation of glucose to yield glucose 6 phosphate serves as the 1st step of what rxns and what enzymes catalyze it
glycolysis and the glycogen synthesis in the liver - hexokinase or glucokinase
Where is hexokinase found, what is its Km and Vmax and what uninduces it
ubiquitous, low Km, high affinity, low capacity low Vmax, uninduced by insulin
Where is glucokinase found, what are the Km and Vmax, and what induces it
liver and beta cells of pancreas, low affinity, high Km, high capacity, high Vmax, induced by insulin
What feedback inhibits hexokinase
glucose-6 phosphate
