principle heme found in Hb and Mb

Heme B

location of heme synth

produced in all cells, synthesis most pronounced in bone marrow and liver

What proteins contain heme?

Mb, Hb, microsomal and mitochondrial cytochromes (electron-transport proteins, iron must be in Fe³⁺ form), enzymes (catalase, peroxidase, tryptophan pyrrolase, prostaglandin synthase, guanylate cyclase, NO synthase)

Heme biosynthesis

location, major enzymes

ALA synthase (E1) and ferrochelatase (E8) act in mitochondria, the intermed. steps take place in cytosol

ALA synthetase

converts succinyl CoA to dALA in first step of heme biosynthesis. 

**rate-limiting step

ingredients needed for heme biosynthesis

succinyl CoA (Kreb's cycle intermediate), glycine residues (from cytosol), iron ion (from cytosol--delivered from liver, where dietary iron is stored)

types of heme

Heme A--cytochrome A

Heme B--Hb, Mb

Heme C--cytochrome C

E7 of heme biosynthetic pathway converts _______ to ____________

protoporphyrinogen to protoporphyrin

occurs in mitochondria

ALAS (name, basic function, location, coenzyme)

ALAS (delta-Aminolevulinic Acid Synthase)

rate-limiting and regulated enzyme

acts in cytosol

vitamin B6 coenzyme

2 ALAS isoforms

ALAS-E (aka ALAS2) erythroid

ALAS-N (aka ALAS1) nonspecific

ALAS regulation

Heme: feedback inhibition (represses transcription and activity)

Iron ion availability: regulates only ALAS-E in developing erythrocytes

sideroblastic anemia

inherited ALAS-E deficiency

X-linked

other causes include copper/lead/zinc poisoning, B6/copper deficiency

Porphyrias (definition)

diseases (hereditary or acquired) characterized by breakdown of heme biosynthetic control mechanisms

Porphyrias (manifestation)

excretion and accumulation of heme biosynthetic intermediates

Porphyrias (cause)

lack of one biosynthetic enzyme, which results in decline in heme levels, causing activation of ALAS expression and activity, which drives accumulation of intermediates

Porphyrias (onset)

hereditary: after puberty, due to appearance of 5β-reductase, used in sex hormone biosynthesis.  Sex hormones stimulate ALAS synthesis

Porphyria classification (by cause and by symptoms)

Cause--acquired and hereditary

Symptoms--neurologic, cutaneous, neurologic-cutaneous (mixed)

Acquired porphyrias

lead poisoning (inhibits ALAS-E)

iron deficiency (protoporphyrin IX is excreted in feces bc it's insoluble)

Neurologic porphyria

Acute intermittent porphyria: due to E3 deficiency, can result in permanant nerve damage or death.  Symptoms caused by elevated ALA.  Tx of acute attacks=hemin injection (represses ALAS transcription in non-erythroid tissues)

Protoporphyria

Cutaneous porphyria

Ferrochelatase (E8) levels are down, causing excretion of protoporphyrin IX in feces.  Liver and erythropoietic tissues affected.

Catabolism of heme-containing proteins

1. degrade globin

2. process hydrophobic products of porphyrin ring cleavage

3. retain/reutilize contained iron

Danger in elimination of heme products

free heme, protoporphyrin degradation products, and free iron are pro-oxidants

free heme is very apolar and very inflammatory

-->CELL INJURY

Heme catabolism: enz and products

enzyme: heme oxygenase, req oxygen and NADPH

heme-->CO (only endogenous source), bilirubin and Fe³⁺

bilirubin sent to liver for further processing,

iron released in ferrous form, bound by ferritin

biliverdin reductase

biliverdin-->bilirubin IX

req NADPH

Ferritin

binds ferrous ion (heme degradation product)

bilirubin

heme degradation product

poorly soluble, therefore needs transporter in blood (albumin)

conjugated with glucuronic acid in liver

bilirubin diglucuronide-->secreted in bile-->intestine-->feces

uridine diphosphoglucuronate

serves as glucuronate donor to bilirubin, making it soluble as bilirubin diglucuronide

conjugated bilirubin

very little in blood, water soluble

elevation-->yellow urine

deposition-->sclera/skin jaundice

unconjugated bilirubin

bound non-covalently to albunin

majority of serum bilirubin

hi affinity for membrane lipids-->impairment of memb fn

covalently-bound bilirubin

covalently-bound to albumin

only present in hepatocellular disease

in some cases, up to 90% of total bilirubin can be in this form

hyperbilirubinemia

elevation in unconjugated bilirubin or elevation in both un- and conjugated bilirubin

accumulation of both unconjugated and conjugated bilirubin

hepatitis, cirrhosis

proportion of conjugated bilirubin increases

accumulation of unconjugated bilirubin

increased production:

hemolysis, ineffective erythropoiesis, massive tissue necrosis or hematomas

decreased clearance:

drug-induced, physiological neonatal jaundice/prematurity, liver diseases(advanced hepatitis/ cirrhosis), Crigler-Najjar syndrome, Gilbert syndrome

Gilbert's syndrome

unconjugated hyperbilirubinemia

neonatal jaundice

Crigler-Najjar syndrome (types, cause)

unconjugated hyperbilirubinemia

autosomal recessive

glucuronyl transferase gene mutation-->bilirubin can't be conjugated

unconj. bilirubin levels rise

type 1 bilirubin encephalopathy (kernicterus) and severe jaundice and brain damage

type 2 lower serum bilirubin conc., no neuro impairmt

neonatal or physiological jaundice

HbF dies off, causing increase in serum bilirubin conc, which developing liver can't handle

usually, self-resolves in a few days as liver matures

can be treated with UV light (makes bilirubin water soluble, excreted in urine)

Anemia

body doesn't have enough healthy blood cells due to:

*underproduction of mature RBCs

*loss of RBCs

Major causes of anemia

inflammation, neoplasia, chronic disease, iron deficiency, maturation disorders, hemolytic anemias, acute bleeding, marrow damage

Major sx of anemia

jaundice, dizziness/fainting, fatigue, low bp, heart attack, angina, splenomegaly, shortness of breath, weakness/fatigue

Idopathic aplastic anemia

bone marrow fails to properly make blood cells

cause: damage to blood stem cells, autoimmune, pregnancy, lupus, toxin/drug exposure (chemo)

RBCs abnormal in shape and form, many damaged

Aase syndrome

bone marrow disorder, marrow poorly developed -->anemia

Fanconi's anemia

defect in proteins that repair DNA, often bone marrow failure-->anemia

Megaloblastic anemia

larger-than-normal RBCs due to folic acid or B12 deficiency (nucleotide/DNA synth)

Pernicious anemia

dec in RBCs when body can't properly absorb B12 from GI tract

hypochromic anemia

less Hb than normal is deposited in the cells

microcytic anemia

small RBCs (low mean corpuscular volume--MCV)

Iron deficiency anemia

20% of women, 50% of pregnant women, 3% of men

caused by: blood loss, poor iron absorption, too little dietary iron, lead poisoning in children

hemolytic anemia

loss of RBCs

intrinsic reasons: abnormalities in RBC proteins, hemoglobinopathies

extrinsic reasons: abnormal immune system response, blood clots in sm vessels, certain infections, medication side effects

Congenital spherocytic anemia

RBC membrane disorder--> spherical RBCs/lysis

can also have elliptocytosis or ovalocytosis

HbSC disease

HbS and HbC point mutations

idiopathic autoimmune hemolytic anemia

immune system destroys body's own RBCs for unknown reason

Immune hemolytic anemia

reduced RBC count due to premature hemolysis, Rh factor difference between mother and fetus or transfusion of blood from donor w diff blood type

Malaria

lyses RBCs (parasite lives in RBC)

Microangiopathic hemolytic anemia (MAHA)

RBCs destroyed as they travel through damaged small blood vessels (intravascular thrombi)