Heme synthesis pathway
“GLASs PHotos of Ugly Corgis, Poodles, & Hounds”
Mito:
—> Glycine + Succinyl-CoA combine to make Aminolevulinic acid (via ALA synthase+ B6 (biotin))
Cyto:
—> Aminolevulinic acid leaves the mito & forms Porphobilinogen (via ALA Dehydrase)
—> Porphobilinogen forms Hydroxymethylbilane (via Porphobilinogen Deaminase/Hydroxymethylbilane synthase)
—> Hydroxymethylbilane forms Uroporphyrinogen III (via Uropophrynogen synthase)
—> Uroporphyrinogen forms Coporhyrinogen III (via Uroporphyrinogen Decarboxylase)
Mito:
—> Corporphyrinogen forms Protoporphyrin IX
—> Protoporphyrin forms Heme (via Ferrochetalase + Fe2+)
‘
Inhibition of Heme synthesis
- Lead (affects which 2 enzymes)
&
Heme & high glucose
Low iron
Lead: inhibits ALA Dehydrase & Ferrochetalase
Heme/hematin/hemenin & high glucose: ALA synthase I (Liver)
Low iron: ALA synthase II (Bone marrow)
Heme synthesis disorders:
Acute intermittent porphyria
“Ads No ACcePtABLe Pain”
Deficient Porphobilinogen Deaminase/Hydroxymethylbilane synthase:
Auto Dom + Late onset
Causes build-up of PBG (Porphobilinogen) & ALA (Cause neurological dysfunction)
Symptoms:
- Anxiety, confusion, Paranoia
- Acute Abdominal pain
- Port-wine urine (sometimes)
DON’T GIVE BARBITUATES or fast
5 P’s:
- Painful abdomen
- Port-wine urine
- Polyneuropathy
- Psych issues
- Precipitated by barbituates
Treat:
- Hematin/hemin
- high CHO diet
Heme synthesis disorders:
Porphyria cutanea tarda
“Ads Heat, PAin, & BuRns”
Deficient Uroporphyrinogen Decarboxylase
Auto DOM + Late onset
Causes build-up of cyclic tetrapyrroles (cause sunlight-induced lesions)
Symptoms:
- Photosensitivity
- Blistering/inflammation of the skin
- Red/Brown urine (build-up of uroporphyrinogen & abnormal liver enzymes)
- Hyperpigmentation
WORSE WITH ALCOHOL
Port-wine urine is due to build-up of which substrate & is associated with what conditions?
Build-up: Uroporphyrinogen
Ass.:
- Hepatitis
- HIV
- Alcoholism
- Oral contraceptives
- Acute int porphyria
- Porphyria cutanea tarda
Anemia types:
Microcytic (less than 80)
“MIcro AnTS”
- Iron deficiency
- ACD
- Thalassemias
- Sideroblastic anemia
Anemia types:
MCV (80-100)
Normocytic-Hemolytic & Intrinsic anemia
“Normal HIGHSchool Pressure”
- G6PD, PK
- Spherocytosis (hereditary
- Paroxysmal nocturnal hemoglobinuria
- Sickle cell
- Hbc
Anemia types:
MCV (80-100)
Normocytic-Hemolytic & Extrinsic anemia
“A NormAl HEMIsphere”
- MAHA
- MIHA
- Auto immune
- Infection
Anemia types:
MVC (80-100)
Normocytic-Nonhemolytic anemia
“NAKed Ass”
- ACD
- Kidney disease
- Aplastic anemia
Anemia types:
Macrocytic-Megaloblastic anemia
“Massive Mega-Bull Frogs”
- Megaloblastic
- B12 Def
- Folate def
Anemia types:
Macrocytic-Megaloblastic: B12 def absorbed in the ileum
“VitAMin B12 in Breakfast Cereal, HeMP, Trout, HeARTy AniMal Meats, & PeAs”
- Risks (Vegans, Atrophic gastritis, Bypass surgery, Tapeworms, ***Percarnious anemia, Crohn’s, AIDS)
- 2-3 yrs Onset
- High methylmalonic acid
- Megaloblastosis
- Peripheral Neuropathy
- Affected MM-CoA & Homocysteine methyltransferase
Anemia types:
Macrocytic-Megaloblastic: Folate def
“FolATe Affects How PregnanT woMen Deliver”
- risks (Preggos, ***Alcoholics, & Drug users (phenytoin & spruce)
- THF (active form via DHFR)
- Affects Thymidylate synthase, Homocysteine methyltransferase, & purine synthesis
- Megaloblastosis (ONLY)
Microlytic anemia: MCV < 80
Iron Deficiency
“IroN BinDs 2-3x Less THen TItanium Without PacKinG”
Iron def:
- Normal ALA
-Bleeding (colon cancer, GI ulcer, Menorrhagia
etc.)
- Diet def (Protein def, ascorbic acid, vit C, or
copper) - Low Ferritin (Fe3+) & Iron (Fe2+) in serum
- Tachycardia, Weakness/parllor, Glossitis, Pica, Koilonychia (spooning nails)
- High TIBC (body wants more iron)
Microcytic anemia:
Sideroblastic anemia
- B6 deficiency
“IOns LAST & RADiatE Colour in Space”
&
- Lead toxicity
“LABS PrOvIde bLADes For iNcisions”
B6 Def:
- Isoniazid (TB patients)
- Low ALA synthase (Low ALA levels mean no
Heme to bind iron)
- Iron overload (high ferritin & iron)
- Low TIBC (the body doesn’t need more iron)
- Reduced AA decarboxylase activity (def GABA,
DA, NE/E = Epileptic convulsions) - Reduced CBS activity (Homocystinemia & risk
DVT/Stroke)
Lead poisoning:
- Lead exposure (paint chips)
- Abdominal pain (unexplained)
- Basophilic Stippling
- Peripheral neuropathy
- Iron Overload (high ferritin & iron)
- Low ALA Dehydrase (High ALA levels)
- Low ferrochelatase (sideroblastosis)
- Low TIBC (the body doesn’t want more iron)
- Neuro-toxic/psychic issues
Microcytic anemia:
Thalassemia
“thAlAssemiA Has Bad CHanges”
Alpha thalassemia:
- 1 deletion = asymptomatic
- 2 deletions = Mild anemia
- 3 deletions = Severe anemia
- 4 deletions = Hydropis fetalis (dead)
Beta thalassemia:
- 1 deletion = Minor B-T
- 2 deletions = Major B-T
(Hgb A2) reduces hematopoiesis in normal bone marrow in long bones, so it happens more in the skull (Chimpmunk Facies)
Microcytic/Normocytic anemia:
ACD (Anemia of Chronic Diseases)
“CD’s in the KAR”
The body can’t tell the difference between chronic inflammation and infection, so it hides its iron from siderophoric bacteria.
It releases Hepcidin (lowers iron reabsorption & increases storage)
Low iron & ferritin
High TIBC
Kidney disease
Autoimmune disease
Rheumatological disease
Normocytic anemia (80-100):
Paroxysmal Nocturnal Hemoglobinuria
“PNH Can DRoP PIGA”
Pancytopenia, Negative Coombes test, & Hibernation (during sleep)
- Complement system isn’t inhibited by CD55/59
- Defective PIGA gene
- Decreased CD55/59
- Premature RBC lyses
Normocytic Intrinsic anemia:
“NO FRee SHots of Gin or FireBall Pay your Dollars”
- No NADPH
- Glutathione isn’t reduced
- Oxidative stress on RBCs
- Free radicals aren’t destroyed
- Sulfa, Dapsone, primaquine, & favabeans
- Heinz bodies + Bite cells
Normocytic Intrinsic anemia:
Hereditary Spherocytosis
“DABS are Cool as SHIt”
- Dsyfunctional RBC membrane protein (Ankyrin, Bands & Spectrin)
- Coombs negative test
- Splenomegaly
- Howell-Jolly bodies
- Indirect Jaundice
Key points of transamination:
“Don’T FRee Pesky NH3”
- its a Double-reaction
- Transaminase (aka aminotransferase) is the enzyme
- it’s Freely Reversible
- PLP (aka B6 derivative is the coenzyme)
- No free Ammonia is liberated
ex.
Alanine aminoTR (ALT)
Serum Glutamate-Pyruvate Transaminase (SGPT)
(Alanine + a-ketoglutarate–>pyruvate + glutamate)
Why is Glutamate so important in the transanimation/urea cycle?
Because it’s the only AA that undergoes oxidative deamination enough to release ammonia to feed the urea cycle
Key points about oxidative deamination:
- Glutamate Dehydrogenase (enzyme)
- Liver mitochondria have GDH
- NAD/NADP (coenzymes)
- Releases NH3 to urea cycle
- Allosterically inhibited (ATP, GTP, NADH)
- Activated (ADP)
- Reversible
AA degradation:
Phenylalanine
Phenylalanine -(BH4)–>
Tyrosine -(BH4)–> (also makes thyroxine)
DOPA -(B6)–> (also makes melanin)
Dopamine -(Vit C)–>
Norepi -(SAM)–>
Epi
AA Degradation:
Glutamate
Glutamate -(B6)–>
GABA & Glutathione
