Biochemistry Flashcards
Heterochromatin
Condensed, appears darker on EM. Sterically inaccessible, thus transcriptionally inactive. Increased methylation, decreased acetylation.
Euchromatin
Less condensed, appears lighter on EM. Transcriptionally active, sterically accessible.
Collagen: Type I
Most common (90%) - Bone (made by osteoblasts), Skin, Tendon, dentin, fascia, cornea, late wound repair
Collagen: Type II
Cartilage (including hyaline), vitreous body, nucleus pulposus
Collagen: Type III
Reticulin - skin, blood vessels, uterus, fetal tissue, early wound repair
Collagen: Type IV
Basement membrane (basal lamina), lens.
Myotonic Dystrophy
Autosomal dominant. CTG trinucleotide repeat expansion in the DMPK gene -> abnormal expression of myotonin protein kinase -> myotonia (eg, difficulty releasing hand from handshake), muscle wasting, cataracts, testicular atrophy, frontal balding, arrhythmia.
Fragile X Syndrome
X-linked dominant inheritance. Trinucleotide repeat in FMR1 gene -> hypermethylation -> decreased expression. Most common inherited cause of intellectual disability (Down syndrome is the most common genetic cause, but most cases occur sporadically).
Findings: post-pubertal macroorchidism (enlarged testes), long face with large jaw, large everted ears, autism, mitral valve prolapse, hypermobile joints.
Down Syndrome
trisomy 21 (nondisjunction in meiosis) Findings: intellectual disability, flat facies, prominent epicanthal folds, single palmar crease, incurved 5th finger, gap between 1st 2 toes, duodenal atresia, Hirschsprung disease, congenital heart disease (eg, ASD), Brushfield spots. Associated with early-onset Alzheimer disease (chromosome 21 codes for amyloid precursor protein), increased risk of AML/ALL. 95% of cases due to meiotic nondisjunction (increased with advanced maternal age; from 1:1500 in women <20 to 1:25 in women >45 years old). 4% of cases due to unbalanced Robertsonian translocation, most typically between chromosomes 14 and 21. Only 1% of cases are due to postfertilization mitotic error.
Edwards Syndrome
trisomy 18
Findings: Prominent occiput, Rocker-bottom feet, Intellectual disability, Nondisjunction, Clenched fists with overlapping fingers, low-set ears, micrognathia (small jaw), congenital heart disease, omphalocele, myelomeningocele. Death usually occurs by age 1 year.
Patau Syndrome
trisomy 13
Findings: severe intellectual disability, rocker-bottom feet, microphthalmia, microcephaly, cleft lip/palate, holoprosencephaly, polydactyly, cutis aplasia, congenital heart disease, polycystic kidney disease, omphalocele. Death usually occurs by age 1.
Osteogenesis Imperfecta
Genetic bone disorder (brittle bone disease) caused by a variety of gene defects (most commonly COL1A1 and COL1A2).
Most common form is autosomal dominant with decreased production of otherwise normal type I collagen. Manifestations include:
Multiple fractures and bone deformities after minimal trauma (eg, during birth)
Blue sclerae due to the translucent connective tissue over choroidal veins
Some forms have tooth abnormalities, including opalescent teeth that wear easily due to lack of dentin (dentinogenesis imperfecta)
Conductive hearing loss (abnormal ossicles)
Ehlers-Danlos Syndrome
Faulty collagen synthesis causing hyperextensible skin, hypermobile joints and tendency to bleed (easy bruising). Multiple types. Inheritance and severity vary. Can be autosomal dominant or recessive. May be associated with joint dislocation, berry and aortic aneurysms, organ rupture. Hypermobility type (joint instability): most common type. Classical type (joint and skin symptoms): caused by a mutation in type V collagen (eg, COL5A1, COL5A2). Vascular type (fragile tissues including vessels [eg, aorta], muscles, and organs that are prone to rupture [eg, gravid uterus]): mutations in type III procollagen (eg, COL3A1).
Menkes Disease
X-linked recessive connective tissue disease caused by impaired copper absorption and transport due to defective Menkes protein (ATP7A, vs ATP7B in Wilson disease). Low copper levels (vs high levels in Wilson disease). Leads to low activity of lysyl oxidase (copper is a necessary cofactor) -> defective collagen. Results in brittle, “kinky” hair, growth retardation, hypotonia, increased risk of cerebral aneurysms.
Lesch-Nyhan Syndrome
Defective purine salvage due to absent HGPRT, which converts hypoxanthine to IMP and guanine to GMP. Results in excess uric acid production and de novo purine synthesis.
X-linked recessive.
Findings: intellectual disability, swollen and painful joints, self-mutilation, aggression, hyperuricemia (orange “sand” [sodium urate crystals] in diaper), gout, dystonia, macrocytosis.
HYPERSEGMENTED NEUTROPHILS
Treatment: Allopurinol or febuxostat (2nd line).
Microfilaments
Muscle contraction, cytokinesis
Intermediate Filaments
Maintain Cell Structure
Microtubules
Movement, cell division
Marfan Syndrome
autosomal dominant (with variable expression) connective tissue disorder affecting skeleton, heart, and eyes. FBN1 gene mutation on chromosome 15 results in defective fibrillin, a glycoprotein that forms a sheath around elastin. Findings: tall with long extremities; pectus carinatum or pectus excavatum; hypermobile joints; long, tapering fingers and toes (arachnodactyly); cystic medial necrosis of aorta; aortic root aneurysm rupture or dissection (most common cause of death); mitral valve prolapse. Subluxation of lenses, typically upward and temporally (vs downward and medially in homocystinuria).
Southern Blot
DNA is cleaved, separated by electrophoresis and transferred to a filter. Filter is exposed to radiolabeled probe that anneals to it’s complementary strand.
Resulting double-stranded, labeled DNA when filter is exposed to film.
Northern Blot
RNA
Western Blot
protein
Southwestern Blot
DNA-binding proteins
Codominance
Both alleles contribute to the phenotype of the heterozygote
Variable expressivity
Patients with the same genotype have varying phenotypes
Incomplete penetrance
Not all individuals with a mutant genotype show the mutant phenotype.
%penetrance x probability of inheriting genotype = risk of expressing phenotype.
Pleiotrophy
One gene contributes to multiple phenotypic effects.
Anticipation
Increased severity or earlier onset of disease in succeeding generations.
Loss of heterozygosity
If a patient inherits or develops a mutation in a tumor suppressor gene, the complementary allele must be deleted/mutated before cancer develops. This is not true of oncogenes.
Dominant negative mutation
Exerts a dominant effect. A heterozygote produces a nonfunctional altered protein that also prevents the normal gene product from functioning.
Linkage disequilibrium
Tendency for certain alleles at 2 linked loci to occur together more or less often than expected by chance. Measured in a population, not in a family, and often varies in different populations.
Mosaicism
Presence of genetically distinct cell lines in the same individual.
Somatic mosaicism - mutation arises from mitotic errors after fertilization and propagates through multiple tissues and organs.
Gonadal mosaicism - mutation only in egg or sperm cells. If parents and relatives do not have the disease, suspect gonadal (or germline) mosaicism.
Locus heterogeneity
Mutations at different loci can produce a similar phenotype.
Allelic heterogeneity
Different mutations in the same locus produce the same phenotype.
Heteroplasmy
Presence of both normal and mutated mtDNA, resulting in variable expression in mitochondrially inherited disease.
Uniparental disomy
Offspring receives 2 copies of a chromosome from 1 parent and no copies from the other parent. Heterodisomy (heterozygous) indicates a meiosis I error. Isodisomy (homozygous) indicates a meiosis II error or postzygotic chromosomal duplication of one of a pair of chromosomes, and loss of the other of the original pair.
Prader-Willi Syndrome
PATERNAL DELETION
Maternally derived genes are silenced.
Disease occurs when the paternal allele is deleted or mutated.
Hyperphagia, obesity, intellectual disability, hypogonadism, hypotonia
Chromosome 15 of paternal origin
Angelman Syndrome
MATERNAL DELETION
Paternally derived UBE3A is silenced
Disease occurs when the maternal allele is deleted or mutated
Seizures, ataxia, severe intellectual disability, inappropriate laughter
UBE3A on maternal copy of chromosome 15
Cystic Fibrosis
Autosomal recessive; defect in CFTR gene on chromosome 7; commonly a deletion of Phe508. Most common lethal genetic disease in Caucasian population.
CFTR encodes an ATP-gated Cl channel that secretes Cl in lungs and GI tract, and reabsorbs Cl in sweat glands. Most common mutation -> misfolded protein -> protein retained in RER and not transported to cell membrane, causing decrease Cl (and H2O) secretion; increase intracellular Cl results in increase Na reabsorption via epithelial Na channels (ENaC) -> increase H2O absorption -> abnormally thick mucus secreted into lungs and GI tract. Increase Na reabsorption also causes more negative transepithelial potential difference
Duchenne
X-linked disorder typically due to frameshift deletions or nonsense mutations -> truncated or absent dystrophin protein -> progressive myofiber damage. Weakness begins in pelvic girdle muscles and progresses superiorly. Pseudeohypertrophy of calf muscles due to fibrofatty replacement of muscle. Waddling gait.
Onset before 5 y/o. Dilated cardiomyopathy is common cause of death.
Becker
X-linked disorder typically due to non-frameshift deletions in dystrophin gene (partially functional instead of truncated). Less severe than Duchenne.
Onset in adolescence or early childhood.
Genetic disorders by chromosome: 4
ADPKD (PKD2)
Achondroplasia
Huntington Disease
Genetic disorders by chromosome: 5
Cri-du-chat syndrome
Familial Adenomatous polyposis
Genetic disorders by chromosome: 7
Williams Syndrome
Cystic Fibrosis
Genetic disorders by chromosome: 21
Down Syndrome
Genetic disorders by chromosome: 18
Edwards Syndrome
Genetic disorders by chromosome: 13
Patau Syndrome
Wilson Disease
Retinoblastoma (RB1)
BRCA2
Cri-du-chat Syndrome
Congenital deletion of short arm of chromosome 5
Findings: microcephaly, moderate to severe intellectual disability, high-pitched crying/meowing, epicanthal folds, cardiac abnormalities (VSD)
Williams Syndrome
Congenital microdeletion of long arm of chromosome 7 (deleted region includes elastin gene).
Findings: distinctive “elfin” facies, intellectual disability, hypercalcemia, well-developed verbal skills, extreme friendliness with strangers, cardiovascular problems (eg, supravalvular aortic stenosis, renal artery stenosis)/
Kwashiorkor
Protein malnutrition resulting in skin lesions, edema due to decrease plasma oncotic pressure, liver malfunction (fatty change due to decrease apolipoprotein synthesis). Clinical picture is small child with swollen abdomen.
Marasmus
Malnutrition not causing edema. Diet is deficient in calories but no nutrients are entirely absent.
Glucose-6-phosphate dehydrogenase deficiency
NADPH is necessary to keep glutathione reduced, which in turn detoxifies free radicals and peroxides. Decrease NADPH in RBCs leads to hemolytic anemia due to poor RBC defense against oxidizing agents (eg, fava beans, sulfonamides, nitrofurantoin, primaquine/chloroquine, antituberculosis drugs). Infection (most common cause) can also precipitate hemolysis; inflammatory response produces free radicals that diffuse into RBCs, causing oxidative damage.
X-linked recessive disorder; most common human enzyme deficiency; more prevalent among African Americans. Increased malarial resistance.
Heinz bodies
Bite Cells
Von Gierke disease
Glycogen storage disease (type I)
Deficient enzyme: glucose-6-phosphatase
Severe fasting hypogylcemia, increase glycogen in liver and kidneys, increase blood lactate, increase triglycerides, increase uric acid (gout), and hepatomegaly, renomegaly. Liver does not regulate blood glucose.
Pompe disease
Glycogen storage disease (type II)
Deficient enzyme: lysosomal acid alpha-1,4-glucosidase (acid maltase) with alpha-1,6-glucosidase activity
Cardiomegaly, hypertrophic cardiomyopathy, hypotonia, exercise intolerance, and systemic finding lead to early death.
Cori disease
Glycogen storage disease (type III)
Deficient enzyme: debranching enzyme (alpha-1,6-glucosidase and 4-alpha-D-glucanotransferase)
Similar to von Gierke disease, but milder symptoms and normal blood lactate levels. Can lead to cardiomyopathy. Limit dextrin-like structure accumulate in cytosol.
McArdle disease
Glycogen storage disease (type V)
Deficient enzyme: Skeletal muscle glycogen phosphorylase (Myophosphorylase)
Increased glycogen in muscle, but muscle cannot break it down -> painful muscle cramps, myoglobinuria (red urine) with strenuous exercise, and arrhythmia from electrolyte abnormalities. Second-wind phenomenon noted during exercise due to increase muscular blood flow.
Tay-Sachs disease
Lysosomal storage diseases
Deficient enzyme: Hexosaminidase A
Progressive neurogeneration, developmental delay, hyperreflexia, hyperacusis, “cherry-red” spot on macular, lysosomes with onion skin, no hepatosplenomegaly (vs Niemann-Pick)
Fabry disease
Lysosomal storage diseases
Deficient enzyme: alpha-galactosidase A
Early: triad of episodic peripheral neuropathy, angiokeratomas, hypohidrosis
Late: progressive renal failure, cardiovascular disease.
Metachromatic leukodystrophy
Lysosomal storage diseases
Deficient enzyme: Arylsulfatase A
Central and peripheral demyelination with ataxia, dementia
Krabbe disease
Lysosomal storage diseases
Deficient enzyme: Galactocerebrosidase
Peripheral neuropathy, destruction of oligodendrocytes, developmental delay, optic atrophy, globoid cells.
Gaucher disease
Lysosomal storage diseases
Deficient enzyme: Glucocerebrosidase
Most common.
Hepatosplenomegaly, pancytopenia, osteoporosis, avascular necrosis of femur, bone crises, Gaucher cells (lipid-laden macrophages resembling crumpled tissue paper)
Niemann-Pick disease
Lysosomal storage diseases
Deficient enzyme: Sphingomyelinase
Progressive neurodegeneration, hepatoslenomegaly, foam cells (lipid-laden macrophages), “cherry-red” spot on macula
Hurler Syndrome
Lysosomal storage diseases
Deficient enzyme: alpha-L-iduronidase
Developmental delay, gargoylism, airway obstruction, corneal clouding, hepatosplenomegaly
Hunter Syndrome
Lysosomal storage diseases
Deficient enzyme: Iduronate-2-sulfatase
Mild hurler + aggressive behavior, no corneal clouding
Phenylketonuria
Due to decrease phenylalanine hydroxylase or decrease tetrahydrobiopterin (BH4) cofactor (malignant PKU). Tyrosine becomes essential. Increase phenylalanine -> increase phenyl ketones in urine.
Findings: intellectual disability, growth retardation, seizures, fair complexion, eczema, musty body odor.
Maple Syrup Urine Disease
Blocked degradation of branched amino acids (Isoleucine, Leucine, Valine) due to decreased branched-chain alpha-ketoacid dehydrogenase (B1). Causes increased alpha-ketoacids in the blood, especially those of leucine.
Alkaptonuria
Congenital deficiency of homogentisate oxidase in the degrative pathway of tyrosine to fumarate -> pigment-forming homogentisic acid builds up in tissue. Autosomal recessive. Usually benign.
Findings: bluish-black connective tissue, ear cartilage, and sclerae (ochronosis); urine turns black on prolonged exposure to air. May have debilitating arthralgias (homogentisic acid toxic to cartilage).
Homocystinuria
All forms result in excess homocysteine.
Elevated homocysteine in urine, osteoporosis, marfanoid habitus, ocular changes (downward and inward lens subluxation), cardiovascular effects (thrombosis and atherosclerosis -> stroke and MI), kyphosis, intellectual disability, fair complexion.
Causes (all autosomal recessive):
- Cystathionine synthase deficiency
- decreased affinity of cystathionine synthase for pyridoxal phosphate
- Methionine synthase deficiency
- Methylenetetrahydrofolate reductase (MTHFR) deficiency
Ornithine transcarbamylase deficiency
Most common urea cycle disorder. X-linked recessive (vs other urea cycle enzyme deficiencies which are autosomal recessive). Interferes with the body’s ability to eliminate ammonia. Often evident in the first few days of life, but may present later. Excess carbamoyl phosphate is converted to orotic acid (part of the pyrimidine synthesis pathway).
Findings: increase orotic acid in blood and urine, decrease BUN, symptoms of hyperammonemia. No megaloblastic anemia (vs orotic aciduria).
Essential fructosuria
Involves a defect in fructokinase. Autosomal recessive. A benign, asymptomatic condition, since fructose is not trapped in cells. Hexokinase becomes primary pathway for converting fructose to fructose-6-phosphate.
Symptoms: fructose appears in blood and urine
Hereditary fructose intolerance
Hereditary deficiency of aldolase B. Autosomal recessive. Fructose-1-phosphate accumulates, causing a decrease in available phosphate, which results in inhibition of glycogenolysis and gluconeogenesis. Symptoms present following consumptions of fruit, juice or honey.
Symptoms: hypoglycemia, jaundice, cirrhosis, vomiting
Galactokinase deficiency
Hereditary deficiency of galactokinase. Galactitol accumulates if galactose is present in diet. Relatively mild condition. Autosomal recessive.
Symptoms: galactose appears in blood (galactosemia) and urine (galactosuria); infantile cataracts.
May present as failure to track objects or to develop a social smile.
Classic galactosemia
Absence of galactose-1-phosphate uridyltransferase. Autosomal recessive. Damage is caused by accumulation of toxic substances (including galactitol, which accumulates in the lens of the eye).
Symptoms develop when infant begins feeding (lactose present in breast milk and routine formula) and include failure to thrive, jaundice, hepatomegaly, infantile cataracts, intellectual disability.
Histone acetylation
Removal of histone’s (+) charge -> relaxed DNA coiling -> increased transcription
Histone deaceylation
Removal of acetyl groups -> tightened DNA coiling -> decreased transcription
Helicase
Unwinds DNA template at replication fork
DNA topoisomerases
Create a single- or double-stranded break in the helix to add or remove supercoils
Primase
Makes an RNA primer on which DNA polymerase III can initiate replication
DNA polymerase III
Prokaryotes only. Elongates leading strand by adding deoxynucleotides to the 3’ end.
Elongates lagging strand until it reaches primer of preceding fragment.
DNA polymerase I
Prokaryotes only. Degrades RNA primer; replaces it with DNA.
DNA ligase
Catalyzes the formation of a phosphodiester bond within a strand of double stranded DNA.
Telomerase
Eukaryotes only. A reverse transcriptase (RNA-dependent DNA polymerase) that adds DNA (TTAGGG) to 3’ ends of chromosomes to avoid loss of genetic material with every duplication.
RNA polymerase I
Eukaryotes.
Makes rRNA, the most common type; present only in nucleolus.
RNA polymerase II
Eukaryotes.
Makes mRNA, miRNA (microRNA), and snRNA (small nuclear RNA)
RNA polymerase III
Eukaryotes.
Makes 5S rRNA, tRNA
alpha-amanitin
Found in Amanita phalloides (death cap mushrooms), inhibits RNA polymerase II.
Causes severe hepatotoxicity if ingested.
Alport Syndrome
Genetic defect in type IV collagen.
Asymptomatic microscopic hematuria gradually develops to hematuria, proteinuria and progressive kidney disease. Sensorineural hearing loss and anterior lenticonus
Statins
First-line medications for treatment of hyperlipidemia.
Competitive inhibitors of HMG-CoA reductase that decrease de novo cholesterol production in the liver. Statins also upregulate LDL cholesterol receptors on the liver’s surface by increasing LDL cholesterol clearance from the bloodstream
Neurofibromatosis 1 (NF1)
Characterized by neurofibromas and cafe-au-lait spots
patients with NF1 may also present with Lisch nodules, which are pigmented nodules on the iris
Hexokinase
Found in most tissues
low Km, low vmax
Glucokinase
Found in liver and pancreas, induced by insulin
high km, high vmax
Vitamin A
Retinal, retinol, retinoic acid
antioxidant; constituent of visual pigments; essential for normal differentiation of epithelial cells into specialized tissue; prevents squamous metaplasia.
Found in liver and leafy vegetables
Vitamin A Deficiency
Night blindness (nyctalopia); dry, scaly skin (xerosis cutis)
Vitamin A Excess
Acute toxicity - nausea, vomiting, vertigo and blurred vision
Chronic toxicity - alopecia, dry skin, hepatic toxicity and enlargement, arthralgias
B1
thiamine
a cofactor for many dehydrogenase enzyme reactions
Branched-chain ketoacid dehydrogenase
alpha-ketoglutarate dehydrogenase (TCA Cycle)
Pyruvate dehydrogenase (TCA Cycle)
Transketolase (HMP Shunt)
Deficiency = impaired glucose breakdown -> ATP depletion
B2
riboflavin
Component of flavins FAD and FMN, used as cofactors in redox reactions
Deficiency = cheilosis (inflammation of lips, scaling and fissures at the corners of the mouth), corneal vascularization
B3
niacin, nicotinic acid
Constituent of NAD+, NADP+. Derived from tryptophan. Synthesis requires vitamins B2 and B6. Used to treat dyslipidemia; lowers levels of VLDL and raises levels of HDL
B5
pantothenic acid
Essential component of coenzyme A and fatty acid synthase
B6
pyridoxine
Converted to pyridoxal phosphate (PLP), a cofactor used in transamination (eg, ALT and AST), decarboxylation reactions, glycogen phosphorylase. Synthesis of glutathione, cystathionine, heme, niacin, histamine and neurotransmitters including serotonin, epinephrine, norepinephrine, dopamine and GABA
B7
biotin Cofactor for carboxylation enzymes Pyruvate carboxylase Acetyl-CoA carboxylase Propionyl-CoA carboxylase
B9
folate
Converted to tetrahydrofolic (THF) acid, a coenzyme fro 1-carbon transfer/methylation reactions.
Important for the synthesis of nitrogenous bases in DNA and RNA
B12
cobalamin
Cofactor for methionine synthase (transfers CH3 groups as methylcobalamin) and methylmalonyl-CoA mutase. Important for DNA synthesis
Vitamin C
ascorbic acid
Antioxidant; also facilitates iron absorption by reducing it to Fe2+ state. Necessary for hydroxylation of proline and lysine in collagen synthesis. Necessary for dopamine beta-hydroxylase, which converts dopamine to NE
Vitamin D
D3 (cholecalciferol)
D2 (ergocalciferol)
Increases intestinal absorption of Ca2+ and PO43-
Increases bone mineralization at low levels
increases bone reabsorption at higher levels
Vitamin E
tocopherol, tocotrienol
antioxidant (protects RBCs and membranes from free radical damage)
Vitamin K
phytomenadione, phylloquinone, phytonadione, menaquinone
activated by epoxide reductase tp the reduced form, which is a cofactor for the gamma-carboxylation of glutamic acid residues on various proteins required for blood clotting. Synthesized by intestinal flora
Wernicke encephalophathy
B1 THIAMINE
acute, life-threatening, neurologic condition; classic triad of confusion, ophthalmoplegia, ataxia
Korsakoff Syndrome
B1 THIAMINE
amnestic disorder due to chronic alcohol consumption; presents with confabulation, personality changes, memory loss (permanent)
Wernicke-Korsakoff Syndrome
B1 THIAMINE
damage to medial dorsal nucleus of thalamus, mammillary bodies. Presentation is combination of Wernicke encephalopathy and Korsakoff syndrome
Dry beriberi
B1 THIAMINE
polyneuropathy, symmetric muscle wasting
Wet beriberi
B1 THIAMINE
high-output cardiac failure (dilated cardiomyopathy), edema
