Hemoglobin Synthesis and Catabolism Flashcards
hemoglobin - properties
heme: porphyrin ring structure with 4 N atoms that chelate 1 Fe2+
globin: 2 pairs of globin protein chains, each w/ 1 heme group
rate-limiting enzyme of heme synthesis
delta-aminolevulinate synthase (ALA synthase)
heme is feedback inhibitor (represses gene synthesis)
first step of heme synthesis
occurs in mitochondria
formation of porphobilinogen
condensation -> (ALA synthase) -> 2ALA -> (PBG synthase) -> porphobilinogen
second step of heme synthesis
occurs in cytosol
formation of heme from protoporphyrin ring and Fe2+
4porphobilinogen -> protoporphyrin + Fe2+ -> (ferrochelatase) -> heme
Pb poisoning - effects
inhibits ferrochelatase and PBG synthase
no new heme production -> no O2 to tissues -> hypoxia
protoporphyria - cause, effects
ferrochelatase mutation
sx: painful photosensitivity
sideroblastic anemia - cause, effects
ALA synthase mutation
high levels of unbound Fe2+ in blood
hypoxia
porphyria - cause, effects
PBG synthase/PBG deaminase mutation
acute and cutaneous forms
acute: abdominal pain, GI sx, muscle weakness, seizures
cutaneous: painful photosensitivity, blistering, itching, swelling
globin synthesis
occurs in cytoplasm
increased heme levels promote globin synthesis
hemoglobin synthesis - determining factors
1) adequate Fe supply (transported from sites of absorption/storage by transferrin through plasma to bone marrow)
2) adequate heme from mitochondria
3) adequate globin from cytosol
compare/contrast different types of hemoglobin
all contain 2 alpha chains
embryonic (Gower’s): zeta + epsilon chains
hemoglobin F (fetal; 1%): 2 gamma chains
hemoglobin A (adult; 97%): 2 beta chains
hemoglobin A2 (alternate; 2%): 2 delta chains
compare/contrast forms of hemoglobin
oxyhemoglobin: oxidized; bound to O2
deoxyhemoglobin: reduced; unbound
methemoglobin: Fe3+ (ferric), unable to carry O2; usually ~3% of Hb; formed by nitrites and sulfonamides; converted back to Fe2+ by methemoglobin reductase
carbaminohemoglobin: bound to CO2
carboxyhemoglobin: bound to CO (produced from heme degradation to bilirubin); usually ~3% of Hb
sulfhemoglobin: oxidized; partially denatured Hb due to sulfonamides or aromatic amines; unable to carry O2
non-heme iron metabolism
absorption occurs in duodenum ONLY
ferrous (2+) or ferric (3+) from diet
ferrous more easily absorbed
1) 3+ -> (ferric reductase) -> 2+ (apical membrane)
2) DMT1 cotransports Fe2+ and H+ into cells
3) ferroportin (mobilferrin) transports Fe2+ across basolateral membrane; regulated by hepcidin
4) 2+ -> 3+, bound to transferrin
heme iron metabolism
absorption occurs in duodenum ONLY
from breakdown of myoglobin/hemoglobin
1) transported by HCP1 or endocytosis
2) heme -> (heme oxygenase) -> Fe3+ released
3) enterocytes convert 3+ -> 2+
4) ferroportin (mobilferrin) transports Fe2+ across basolateral membrane; regulated by hepcidin
5) 2+ -> 3+, bound to transferrin
iron storage - how regulated, where
Fe bound to apoferritin -> ferritin
deposited in liver and reticuloendothelial system (RES)
apoferritin stores and releases iron as necessary -> “iron buffer”
