Heme Biosynthesis Flip Class Flashcards
Structure of heme
4 pyroles (pent with N at top and two double bonds)
Either methyl, vinyl, or propionate
-arrangement of side chains is important for activity
Fe+2
Heme aka
Protophyrin IX
p450 class enzymes
Synthesized by heme
In liver-liver detox, synthesis of vit D, cholesterol syn, synthesis of bile and bile acids
Decrease in these enzymes leads to heme biosyn
Incrased sun after 4M
Porphyrin precursors
ALA and PBG
Water soluble and are excreted and measured in urine
Porphyrinogens
Larger-aqueous stability varies based on number of carboxylic acid (acidic) side chains
Biologiacally active
Reduced
Porphyrins
Detected and measured in a labs
Oxidized-creates conjugation system that allows molecules to abosrt visible light
-Produces reactive species in tissue
Heme biosynthesis pathway
8 steps
Succinyl CoA+glycine -delta aminolevunlinic acid synthase 2 Delta aminovulnic acids -delta aminovulinic acid dehhydratase 4 Porphobilinogen -Porphobilinogen deaminase Hyroxymethbilane -UROIII Cosynthase UROIII -URO Decarboxlyase COPROIII -Copro Oxidase (all phyrinogen above) Protophyrinogen IX -Proto oxidase Protophyrin 9 -Ferrochelatase and Fe2+ Heme
what parts of heme biosyn are in mito
succinyal coa and glycine to ALA
and
Copro III to Heme
ALAS=
Vit B6
Pyridoxal phosphate
Committed step?
ALAS
Inhibited by Fe
ALAS II
Inhibited by Pb
ALAD, Ferro (less sensitive), Pyrimidine 5’ nucleotides
Where is heme syn?
Bone marrow (85%) Liver
What stops heme syn
RBC mature
1st step
Sucinyal CoA and glycine to delta Aminivulinate
b6
ALAS1 or housekeeping in liver
ALAS2 (inhabit by Fe)
1st step inhib
difference with ALASII
hematin, hemin heme,(allosteric inhib)
Heme (inhibits alas to cyto)
Heme, insulin , glucose-repress trx of ALAS
Has IRE-translation blocked by Pb
2nd step
2 molecules ALA to PBG by ALAD
ALAD contains Zn
1st precursor pyrole
Inhibited by Pb
1st step activation
4M
Liver-metabolize p450 stuff
induce sun of p450-need heme
decrease concentration of heme in cells
4m
meds, maladies, bleeding, malnutrition
increase p450 sun
3rd step
4PBG+PBGD=HMB
4th step
HMB+UROIIIS=UROIII+UROIIID=COPROI
or
high conc
HMB spont to UROI spont to COPROI
URO III, COPROIII, Protophyrinogen IX
excretion
urine, urine and blie, blie
Siderblastic anemia
ring siderblasts in bone marrow (excessive Fe accumulation)
Impaired heme biosyn
Microcytic and hypochromic
Mito metabolism problems
Nucleated RBC
hereditary sidero anemia
X-linked-erythroid spec=ALAS2
mtDNA mistake
Aquired
Myedisplasia-mtDNA pt muts
Drugs-Isoniazid/ethanol
Toxins-lead
Nutritional-pyrixidoxine defeciency
Trx Pb poisoning
chelators
Pb poisioning presentation
lethary, ab discomfort,
anemia, gingival and long bone pb line, headache
convulsions, coma, renal failure
Diagnosis of Pb poisoning
ALA in urine
ZPP in blood (goes into protophyrin 9 instead of Fe)
Basophilic stippling in peripheral smear
Acute porphyria vs nonacute
acute-ALA/PBG up, decrease in heme-neuropsych signs and symtoms
Nonacute-accumulation of porphyrinogens in skin and tissue, spontaneous oxidation of porhyringens to porphyrins, photosenstivity
acute and non acute porphyria sims
mostly auto dom
both have genetic and non genetic factors
(some are auto rec tho)
AIP
PBGD defieciency
Symptoms of AIP
Accumulation of ALA and PBG
-neurotoxic levels
NO SKIN LESIONS
Gi disorder, psych disorders,
all at risk for liver cancer
Attack of AIP after 4M
2nd most common
PBG in urine
Brown/Red
AIP trx
Avoid 4M, glucose loading, admin hemin/hematin, stop p450 syn
DECREASE ALA SYN
PTC
UROD Problem
Acquired or autu dominant (familial PCT)
Factors affect PTC onset
and symptoms
4th/5th decade onset
alc, fe overload, sunligh, HIV/HEP C/B
bullae, hypertrichosis, heliotrope, sclerodermoid plaque, dark urine, milia
milia, bullae, hypertrichosis, helitrope
milic-small white bumps in skin
hypertrichosis-har growing in weird splot
bullate-fluid filled blister (large)
heliprope-purple-red face skin
What causes bad things in PTC
ring intermediates getting hit by sunlight and become reactive O2 species
PTC diagnosis
Uro to copro 3:1 instead or 5:1
more 8-7 carboxyl porphyrin fractions
UROD in blood analysis
Trx for PTC
No env exosures
Sunscreen
Fe Chelator
Bleeding (reduces Fe stores and heme syn up)
EPP
Autodom
Ferrochelatase mutation
Early childhood presentation
SEVERE PHOTOSENSTIVITY
Chornic liver diease
