oxidative deamination

removes amino group, converting C to U

if this strand is used as a template, uracil is base-paired with A, resulting in overall change of C-->T

Apurination/apyrimidination

loss of a purine or pyrimidine base

O⁶-methyl guanosine

highly mutagenic species

T-T dimerization

blocks DNA polymerase, prevents replication

Nitrous acid deamination

A--> hypoxanthine

G-->xanthine

conservative mutation

aa is changed to another aa of similar size and chemical nature

generally does not change protein structure

non-conservative mutation

when an aa is changed to another aa of different size or chemical nature

usually-->change in protein structure

invariant amino acids

aa at functionally active site whose change can result in loss of function

missense mutation

base change causes coding for different aa

nonsense (termination) mutation

codon that codes for aa is mutated to form termination codon

Who discovered the molecular basis/heritability of SCD and in what year?

Linus Pauling 1945

read-through mutation

mutation of a termination codon that results in larger than normal protein

framshift mutation

insertion/deletion of a single nucleotide

causes shift in 3-base codon reading frame

very bad

transition mutation

purine-pyrimidine pair substituted for another

ex: A-T --> G-C

transversion mutation

purine-pyrimidine pair subbed for a pyrimidine-purine pair

ex: A-T --> T-A

peptide mapping or fingerprinting

protein can be sequenced to det. primary structure and compared to a normal protein

cleaved into small frags by digestion w trypsin/pepsin/another enz, then sep by gel electrophoresis

spots compared

can separate abnormal spots and sequence protein

hemoglobinopathies most frequently arise from mutations in the __ gene

beta

Heinz bodies

aa mutations can result in unstable Hb (ex: proline subbed in alpha helix sequence) that easily denature and precipitate as Heinz bodies

unstable Hb

caused by mutation, results in precipitation/denaturation (Heinz bodies)

may cause reticulocytosis, anemia, splenomegaly, urobilinuria

Hb mutation that results in changed o2 affinity

ex: due to substitution of aa that bind BPG or release Bohr protons

Heinz body formation, hemolytic anemia

Hb_Cowtown^{Beta-His-->Leu}

Loss of His that dissociates 50% of Bohr protons

leads to destabilization of T conformation-->inc oxygen affinity

Methemoglobin

HbM

oxidation of ferrous ion to ferric state (mut in heme binding cavity of distal/prox His)

>10% HbM-->cyanosis

>35%-->clinical symptoms

>80%=incompatible w life

diaphorase deficiency

diaphorase reduces ferric back to ferrous state

deficiency-->too much ferric-->methemoglobinemia

Thalassemia

imbalance in production of alpha and beta Hb chains

RBCs are microcytic and hypochromic

β-thalassemias

synth of beta-globin gene is decreased or absent

alpha globin chains for tetramers-->precipitation-->cell death

HbF and HbBart (gamma tetramer) accumulation is typical

β-thal major and minor

minor/trait: heterozygous, make some adult Hb, don't require tx

major aka Cooley's disease: homozygous, babies in 1st yr of life = very sick and require transfusions, results in iron overload and death 15-25.  Tx also includes bone marrow transplantation

HbBart's

gamma globin tetramer found in pts w thalassemia

alpha thalassemia

2 copies of alpha globin gene on each copy of chrom 16

(4 total)

1 defective=silent carrier, no sx

2=alpha thal trait w mild anemia

3=hemoglobin H disease, mild-sever hemolytic anemia

4=hydrops fetalis, fetal death (alpha chain necessary for HbF)

oxygen binding of HbBart's and HbH (gamma4 and beta4)

no cooperativity, therefore high oxygen affinity, useless for carrying oxygen to tissues

HbC and HbS

HbS: 6th beta chain aa, Glutamate, is mutated to Valine

HbC: same Glutamate is mutated to Lysine

acquired hemoglobinemia

CO poisoning

CO binds ferrous ion stronger than O2 does

Tx: 100% O2