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Heme Metabolism
Cs-Szabo
54
Biochemistry
Professional
09/29/2011

Additional Biochemistry Flashcards

 


 

Cards

Term

 

 

 

principle heme found in Hb and Mb

Definition

 

 

 

Heme B

Term

 

 

 

 

location of heme synth

Definition

 

 

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

Term

 

 

 

What proteins contain heme?

Definition

 

 

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)

Term

 

 

 

 

Heme biosynthesis

location, major enzymes

Definition

 

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

 

 

Term

 

 

 

ALA synthetase

Definition

 

 

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

 

**rate-limiting step

Term

 

 

ingredients needed for heme biosynthesis

Definition

 

 

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

Term

 

 

types of heme

Definition

 

 

Heme A--cytochrome A

Heme B--Hb, Mb

Heme C--cytochrome C

Term

 

 

 

 

E7 of heme biosynthetic pathway converts _______ to ____________

Definition

 

 

protoporphyrinogen to protoporphyrin

 

occurs in mitochondria

Term

 

 

 

 

 

ALAS (name, basic function, location, coenzyme)

Definition

 

 

 

 

ALAS (delta-Aminolevulinic Acid Synthase)

rate-limiting and regulated enzyme

acts in cytosol

vitamin B6 coenzyme

Term

 

 

 

2 ALAS isoforms

Definition

 

 

ALAS-E (aka ALAS2) erythroid

 

ALAS-N (aka ALAS1) nonspecific

Term

 

 

 


ALAS regulation

Definition

 

 

Heme: feedback inhibition (represses transcription and activity)

 

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

Term

 

 

 

 

 

sideroblastic anemia

Definition

 

 

inherited ALAS-E deficiency

X-linked

 

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

Term

 

 

 

 

Porphyrias (definition)

Definition

 

 

 

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

Term

 

 

 

Porphyrias (manifestation)

Definition

 

 

 

excretion and accumulation of heme biosynthetic intermediates

Term

 

 

 

Porphyrias (cause)

Definition

 

 

 

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

Term

 

 

 

 

Porphyrias (onset)

Definition

 

 

 

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

Term

 

 

 

 

Porphyria classification (by cause and by symptoms)

Definition

 

 

Cause--acquired and hereditary

 

 

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

Term

 

 

 

 

 

Acquired porphyrias

Definition

 

 

lead poisoning (inhibits ALAS-E)

 

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

Term

 

 

 

 

Neurologic porphyria

Definition

 

 

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)

Term

 

 

 

 

Protoporphyria

Definition

 

 

Cutaneous porphyria

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

Term

 

 

 

Catabolism of heme-containing proteins

Definition

 

1. degrade globin

2. process hydrophobic products of porphyrin ring cleavage

3. retain/reutilize contained iron

Term

 

 

 

 

Danger in elimination of heme products

Definition

 

 

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

 

free heme is very apolar and very inflammatory

 

 

-->CELL INJURY

Term

 

 

 

Heme catabolism: enz and products

Definition

 

 

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

Term

 

 

 

biliverdin reductase

Definition

 

 

 

biliverdin-->bilirubin IX

req NADPH

Term

 

 

 

 

 

Ferritin

Definition

 

 

 

binds ferrous ion (heme degradation product)

Term

 

 

 

 

bilirubin

Definition

heme degradation product

 

poorly soluble, therefore needs transporter in blood (albumin)

conjugated with glucuronic acid in liver

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

Term

 

 

 

 

uridine diphosphoglucuronate

Definition

 

 

 

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

Term

 

 

 

 

conjugated bilirubin

Definition

 

 

 

 

very little in blood, water soluble

elevation-->yellow urine

deposition-->sclera/skin jaundice

Term

 

 

 

unconjugated bilirubin

Definition

 

 

 

bound non-covalently to albunin

majority of serum bilirubin

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

Term

 

 

 

 

 

covalently-bound bilirubin

Definition

 

 

covalently-bound to albumin

only present in hepatocellular disease

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

Term

 

 

 

 

 

hyperbilirubinemia

Definition

 

 

 

 

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

Term

 

 

 

accumulation of both unconjugated and conjugated bilirubin

Definition

 

 

hepatitis, cirrhosis

 

proportion of conjugated bilirubin increases

Term

 

 

 

 

accumulation of unconjugated bilirubin

Definition

 

 

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

Term

 

 

 

Gilbert's syndrome

Definition

 

 

unconjugated hyperbilirubinemia

 

neonatal jaundice

Term

 

 

 

Crigler-Najjar syndrome (types, cause)

Definition

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

 

 

Term

 

 

 

neonatal or physiological jaundice

Definition

 

 

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)

Term

 

 

 

 

Anemia

Definition

 

 

 

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

*underproduction of mature RBCs

*loss of RBCs

Term

 

 

 

Major causes of anemia

Definition

 

 

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

Term

 

 

 

Major sx of anemia

Definition

 

 

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

Term

 

 

 

 

Idopathic aplastic anemia

Definition

 

 

 

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

Term

 

 

 

 

Aase syndrome

Definition

 

 

 

bone marrow disorder, marrow poorly developed -->anemia

Term

 

 

 

Fanconi's anemia

Definition

 

 

 

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

Term

 

 

 

 

 

Megaloblastic anemia

Definition

 

 

 

 

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

Term

 

 

 

 

 

Pernicious anemia

Definition

 

 

 

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

Term

 

 

 

 

 

hypochromic anemia

Definition

 

 

 

 

less Hb than normal is deposited in the cells

Term

 

 

 

 

 

microcytic anemia

Definition

 

 

 

small RBCs (low mean corpuscular volume--MCV)

Term

 

 

 

Iron deficiency anemia

Definition

 

 

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

Term

 

 

 

 

hemolytic anemia

Definition

 

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

Term

 

 

 

 

 

Congenital spherocytic anemia

Definition

 

 

RBC membrane disorder--> spherical RBCs/lysis

 

can also have elliptocytosis or ovalocytosis

Term

 

 

 

 

HbSC disease

Definition

 

 

 

HbS and HbC point mutations

Term

 

 

 

 

idiopathic autoimmune hemolytic anemia

Definition

 

 

 

 

immune system destroys body's own RBCs for unknown reason

Term

 

 

 

 

Immune hemolytic anemia

Definition

 

 

 

 

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

Term

 

 

 

 

 

Malaria

Definition

 

 

 

 

lyses RBCs (parasite lives in RBC)

Term

 

 

 

 

Microangiopathic hemolytic anemia (MAHA)

Definition

 

 

 

 

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

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