FA Biochemistry Flashcards
Orotic Aciduria
- inability to convert orotic acid to UMP
- increased orotic acid in urine; megaloblastic anemia (does not improve with B12 or folate); failure to thrive
Treatment: oral uridine administration
Leflunomide
Inhibits dihydroorotate dehydrogenase
Hydroxyurea
Inhibits ribonucleotide reductase
Mycophenolate and Ribavirin
inhibit IMP hydrogenase
6-Mercaptopurine (6-MP)
inhibits de novo purine synthesis
5-fluorouracil
inhibits thymidylate synthase (decrease deoxythymidine monophosphate)
Methotrexate
inhibits dihydrofolate reductase in humans
Trimethoprim
inhibits dihydrofolate reductase in bacteria
Pyrimethamine
inhibits dihydrofolate reductase in protozoa
Adenosine deaminase deficiency
excess ATP and dATP imbalances nucleotide pool via feedback inhibition of ribonucleotide reductase –> prevents DNA synthesis
– dec lymphocyte could (major cause of autosomal recessive SCID)
Fluoroquinolones
inhibit DNA gyrase (prokaryotic topoisomerase II)
– prevents bacterial division
Transition Mutation
purine to purine
pyrimidine to pyrimidine
Transversion Mutation
purine to pyrimidine
pyrimidine to purine
Missense Mutation (+ example)
Nucleotide substitution resulting in changed amino acid.
Sickle cell disease
Nonsense Mutation
Results in early stop codon
Frameshift Mutation (+ example)
deletion or insertion of a number of nucleotides not divisible by 3 –> msireading of all nucleotides downstream
– usually results in non-functional protein
– throws off “commaless sequence”
Duchenne muscular dystrophy (deleted dystrophin): X Linked
Mismatch Repair Disease
Lynch Syndrome (hereditary nonpolyposis colorectal cancer: HNPCC) - Autosomal Dominant
Nucleotide Excision Repair Disease
Xeroderma Pigmentosum: prevents repair of pyrimidine dimers from UV light exposure
Nonhomologous End Joining Disease
Mutated in ataxia telangiectasia:
- defects in ATM gene; breaks result in cell cycle arrest
Triad: cerebellar defects (Ataxia), spider Angiomas, and IgA deficiency
Antibodies to spliceosome snRNPs
anti-Smith antibodies
highly specific for SLE
anti-U1 RNP antibodies
highly associated with mixed connective tissue disorder
Enzyme for Charging tRNA
Aminoacyl-tRNA synthetase
– attaches amino acid to CCA 3’ end of the rRNA
(CCA: Can Carry Amino acids)
Cells rich in rER
Mucus-secreting goblet cells of the small intestine
Antibody-secreting plasma cells
— synthesis of secretory proteins
Cells rich in sER
Liver hepatocytes
Steroid Hormone-Producing cells of the Adrenal Cortex and Gonads
– sites of steroid synthesis and detoxification of drugs and poisons
Peroxisome
catabolism of very-long-chain fatty acids, branched-chain fatty acids, and amino acids
(beta: oxidation: long-chain fatty acid degradation occurs in mitochondria)
I-cell disease
inclusion cell disease: inherited lysosomal storage disorder
- defect in phosphotransferase: failure of the Golgi to phosphorylate mannose residues (dec mannose-6-phosphate) on glycoproteins –> proteins secreted extracellularly rather than delivered to lysosomes
Proteasome (+ disease implication)
degrades damaged or ubiquitin-tagged proteins
- defects in the ubiquitin-proteasome system have been implicated in some cases of Parkinson disease
Kartagener Syndrome
primary ciliary dyskinesia
- immotile cilia due to a dynein arm defect
- male (immotile sperm)and female (dysfunctional fallopian tube cilia) infertility
- cause bronchiectasis, recurrent sinusitis, and situs inversus
Histochemical Stain for Intermediate Filament: Vimentin
Connective Tissue
Histochemical Stain for Intermediate Filament: Desmin
Muscle
Histochemical Stain for Intermediate Filament: Cytokeratin
Epithelial Cells (keratinized)
Histochemical Stain for Intermediate Filament: GFAP
Neuroglia (Astrocytes)
Histochemical Stain for Intermediate Filament: Neurofilaments
Neurons
Type I Collagen
Bone (made by osteoblasts), skin, tendons;
late wound repair
dec production in osteogenesis imperfecta Type 1
Type II Collagen
Cartilage; vitreous body, nucleus pulposus
Type III Collagen
Reticulin: skin, blood vessels, uterus, fetal tissue, granulation tissue
Type III: Deficient in the vascular type of Ehlers-Danlos syndrome (ThreE D): this is NOT the common type of Ehlers-Danlos
Type IV Collagen
Basement membrane, basal lamina, lens Glomeruli of kidney; capsule of lens Under the FLOOR (basement membrane) - Defect in Alport syndrome - targeted by antibodies in Goodpasture Syndrome
Collagen Synthesis (inside fibroblasts)
- Synthesis (RER): translation of collagen alpha chains (preprocollagen) - usually Gly-X-Y (with X and Y as prline and lysine)
- Hydroxylation (RER): Hydroxylation of specific proline and lysine residues (requires vitamin C: deficiency -> scurvy)
- Glycosylation (RER): Glycosylation of pro-alpha-chain hydroxylysine residues and formation of procollagen via hydrogen and disulfide bonds (triple helix of 3 collagen alpha chains). Problems –> ostogenesis imperfecta
- Exocytosis: of procollagen into extracellular space by Golgi
Collagen Synthesis (outside fibroblasts)
- Proteolytic Processive: cleavage of disulfide-rich terminal regions of procollage, transforming it into insoluble tropocollagen
- Cross-linking: reinforcement of many staggered tropocollagen molecules by covalent lysine-hydroxylysine cross-linkage (by Cu2+ - containing lysyl oxidase) to make collagen fibrils. Problems with cross-linking –> Ehlers-Danlos
Ehlers-Danlos Syndrome
faulty collagen synthesis: hyperextensible skin, tendency to bleed (easy bruising), and hypermobile joints
- associated with joint dislocation, berry and aortic aneurysms, and organ rupture
Menkes Disease
connective tissue disease caused by impaired copper absorption and transport. Leads to dec activity of lysyl oxidase (copper is a necessary cofactor).
Brittle, kinky hair, growth retardation and hypotonia
Marfan Syndrome
defect in fibrillin-1 gene: glycoprotein that forms a sheath around elastin; AD
connective tissue disorder affecting skeleton, heart and eyes. Cystic medial necrosis of aorta –> aortic incompetence and dissecting aortic aneurysms; floppy mitral valve
Elastin
rich in proline and glycine: nonhydroxylated forms (difference from collagen)
- stretchy protein with skin, lungs, large arteries, elastic ligaments, vocal cords, ligamenta flava
- broken down by elastase (which is normally inhibited by alpha-antitrypsin)
Variable Expressivity (+ example)
Phenotype varies among individuals with same genotype.
2 patients with Neurofibromatosis Type I (NF1) may have varying disease severity. But they both express it to some degree
Incomplete Penetrance (+ example)
Not all individuals with a mutant genotype show the mutant phenotype.
BRCA1: do not always result in cancer
Pleiotropy (+ example)
one gene contributes to multiple phenotypic effects
PKU: untreated phenylketonuria manifests with light skin, intellectual disability, and musty body odor.
Loss of heterozygosity (+ example)
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 (gain of function mutations)
ex: retinoblastoma and the two-hit hypothesis
Dominant Negative Mutation
heterozygote produces a nonfunctional altered protein that also prevents the normal gene product from functioning
- mutation of a transcription factor in its allosteric site: nonfunctioning mutant can still bind DNA, preventing the wild-type TF from binding
Linkage Disequilibrium
tendency for certain alleles at 2 linked loci to occur together more often than expected by change
Mosaicism (+ example)
presence of genetically distinct cell lines in the same individuals: arises form mitotic errors after fertilization
- somatic mosaicism: mutation propagates through multiple tissues or organs
McCune-Albright syndrome: is lethal if the mutation is somatic but survivable if mosaic
Locus heterogeneity (+ example)
Mutations at different loci can produce a similar phenotype.
Albinism can be caused by different mutations (melanin production or melanin transport)
Allelic Heterogeneity (+ example)
different mutations in the same locus produce the same phenotype. beta-thalassemia
Heteroplasmy
present of both normal and mutated mtDNA: resulting in variable expression in mitochondrial inherited disease
- the earlier the mutation occurs, the more cells that have the mutated DNA
Polygenic
group of non-allelic genes that together influence a phenotypic trait. Multiple factors; Multiple gene inheritance
examples: androgenetic alopecia (male pattern baldness)
Imprinting (+ example)
one allele is imprinted/inactivated by methylation. with one allele inactivated, deleted of the active allele –> disease
Prader-Willi and Angelman Syndrome
Uniparental Disomy
offspring receives 2 copies of chromosome from one parent and no copies from the other
- heterodisomy: indicates a meiosis I error
- isodisomy: indicates a meiosis II error
Prader-Willi Syndrome
maternal imprinting
Paternal gene is deleted/mutated and maternal gene is normally silent
- results in hyperphagia, obesity, intellectual disability, hypogonadism, and hypotonia
Angelman Syndrome
paternal imprinting
Maternal gene is deleted/mutated and gene from dad is normally silent
- results in inappropriate laughter (happy puppet), seizures, ataxia, and severe intellectual disability
Mitochondrial Myopathies
mitochondrial inheritance:
- myopathy, lactic acidosis and CNS disease
secondary to failure in oxidative phosphorylation
– muscle biopsy shows “ragged red fibers”
Hypophosphatemic Rickets
inherited disorder resulting in increased phosphate wasting at proximal tubule
X linked dominant
Cystic Fibrosis
Autosomal Recessive mutation in CFTR (chr 7): Deletion of Phe508. Misfolded protein.
ATP-gated Cl- channel that secretes Cl- in lungs and GI tract and reabsorbs Cl- in sweat glands.
Duchenne Muscular Dystrophy
X-linked frameshift mutation (deleted dystrophin: DMD)
- pseudohypertrophy of calf muscles
Becker Muscular Dystrophy
X-linked point mutation
onset in adolescence or early adulthood
22q11 Deletion
CATCH-22
Cleft Palate; Abnormal Facies; Thymic aplasia (T cell deficiency); Cardiac defects; Hypocalcemia (secondary to parathyroid aplasia)
Kwashiorkor
protein malnutrition resulting in skin lesions, edema, liver malfunction (fatty changes due to dec apolipoprotein synthesis) - small child with swollen belly results from protein deficient MEAL: Malnutrition Edema Anemia Liver (fatty)
Marasmus
total calorie malnutrition: tissue and muscle wasting, loss of subcutaneous fat and variable edema
Marasmus results in Muscle wasting
RDE: Glycolysis
phosphofructokinase-1
+ AMP, fructose-2,6-bisphosphate
- ATP, citrate
RDE: Gluconeogenesis
fructose-1,6-bisphosphatase
+ ATP, acetyl-CoA
- AMP, fructose-2,6-bisphosphate
RDE: TCA Cycle
isocitrate dehydrogenase
+ ADP
- ATP, NADH
RDE: Glycogenesis
Glycogen synthase
+ glucose-6-phosphate, insulin, cortisol
- glucose-6-phosphate, glucagon
RDE: Glycogenolysis
Glycogen phosphorylase
+ epinephrine, glucagon, AMP
- glucose-6-phosphate, insulin, ATP
RDE: HMP Shunt
glucose-6-phosphate dehydrogenase (G6PD)
+ NADP+
- NADPH
RDE: de novo pyrimidine synthesis
carbamoyl phosphate synthetase II
RDE: de novo purine synthesis
glutamine-phosphoribosylpyrophosphate (PRPP) amidotransferase
- AMP, IMP (inosine monophosphate), GMP
RDE: Urea cycle
carbamoyl phsophate synthetase I
+ N-acetylglutamate
RDE: Fatty acid synthesis
acetyl-CoA carboxylase (ACC)
+ insulin, citrate
- glucagon, palmitoyl-CoA
RDE: Fatty acid oxidation
Carnitine acyltransferase I
- malonyl-CoA
RDE: Ketogenesis
HMG-CoA synthase
RDE: Cholesterol Synthesis
HMG-CoA reductase
+ insulin, thyroxine
- glucagon, cholesterol
Hexokinase
most tissues; high affinity but low Vmax (capacity)
- can work when there are tiny amounts of glucose
Glucokinase
liver only; most active post meal
low affinity but high Vmax
Rotenone
inhibits Complex I of ETC
causes dec proton gradient and block of ATP synthesis
Antimycin A
inhibits Complex III of ETC
causes dec proton gradient and block of ATP synthesis
Cyanide
inhibits Complex IV of ETC
causes dec proton gradient and block of ATP synthesis
Carbon Monoxide
inhibits Complex IV of ETC
causes dec proton gradient and block of ATP synthesis
Oligomycin
inhibits Complex V of ETC (ATP synthase).
No ATP is produced as the chain stops
Uncoupling Agents
increase permeability of mitochondria membrane: causing dec in proton gradient and inc O2 consumption. ATP synthesis stops but electron transport continues. Produces heat
Pleiotropy (+ example)
One gene contributes to multiple phenotypic effects. Untreated phenylketonuria: light skin, intellectual disability, and musty body order. Homocysteinuria is another.
Genetic Heterogeneity
mutation of different genes causes similar phenotype (this is NOT allelic heterogeneity: SAME locus/different mutation)
Allelic Heterogeneity
different mutation at the SAME locus produce similar phenotype (beta-thalassemia)
Locus Heterogeneity
same as genetic hetergeneity (mutation of different genes causes similar phenotype).
Polygenic
Polygene, multiple factor, multiple genes in inheritance. Group of non-allelic genes that together influence a phenotypic trait. Ex: androgenetic alopecia (male pattern baldness)
ApoA-I
LCAT activation (cholesterol esterification)
ApoB-48
Chylomicron assembly and secretion by the intestine
ApoB-100
LDL particle uptake by extrahepatic cells
ApoC-II
Lipoprotein lipase activation
ApoE3 and 4
VLDL and chylomicron remnant uptake by liver cells
