Red blood cells

 are highly specialized cells whose primary function is to deliver oxygen to,
and remove carbon dioxide from, body tissues.
 Mature red blood cells have no nucleus or DNA. Instead, they are filled
with the red pigment hemoglobin.
 Red blood cell formation occurs in the bone marrow, and about 200 billion
new red blood cells are formed daily.
 The life span of a red blood cell is about four months.
 The oxygen-carrying ability of red blood cells is due to the protein
hemoglobin present in such cells.
Hemoglobin
 is a conjugated protein; the protein portion is called globin, and the
prosthetic group (nonprotein portion) is heme.
 Heme contains four pyrrole groups joined together with an iron atom in
the center.
It is the iron atom in heme that interacts with O2, forming a reversible complex
with it. This complexation increases the amount of O2 that the blood can carry
by a factor of 80 over that which simply “dissolves” in the blood.
Old red blood cells are broken down in the spleen (primary site) and liver
(secondary site). Part of this process is degradation of hemoglobin. The globin
protein is hydrolyzed to amino acids, which become part of the amino acid pool.
The iron atom of heme becomes part of ferritin, an iron-storage protein, which
saves the iron for use in the biosynthesis of new hemoglobin molecules. The
tetrapyrrole carbon arrangement of heme is degraded to bile pigments that are
eliminated in feces and to a lesser extent in urine. Degradation of heme begins
with a ring-opening reaction in which a single carbon atom is removed. The
product is called biliverdin.
This reaction has several important characteristics.
1. Molecular oxygen, O2, is required as a reactant.
2. Ring opening releases the iron atom to be incorporated into ferritin.
3. The product containing the excised carbon atom is carbon monoxide (a
substance toxic to the human body).
The carbon monoxide so produced reacts with functioning hemoglobin, forming a
CO–hemoglobin complex; this decreases the oxygen-carrying ability of the blood.
CO–hemoglobin complexes are very stable; CO release to the lungs is a slow
process. ▼ An alternative rendering of the structure of biliverdin is:
This structure employs a notation, common in heme chemistry, in which letters
are used to denote attachments to the pyrrole rings; such notation easily
distinguishes the attachments. The structure’s linear arrangement of pyrrole
rings also saves space compared to the heme-like representation of the rings.
However, the linear structure incorrectly implies that the arrangement of the
pyrrole rings that results from the ring opening is linear (straight-line); rather, the
pyrrole rings actually have a heme-like arrangement
In the second step of heme degradation, biliverdin is converted to bilirubin.
This change involves reduction of the central methylene bridge of biliverdin. ▼
The change from heme to biliverdin to bilirubin usually occurs in the spleen. The
bilirubin is then transported by serum albumin to the liver, where it is
rendered more water soluble by the attachment of sugar residues to its
propionate side chains (P side chains). The solubilizing sugar is glucuronate
(glucose with a-COO− group on C6 instead of a-CH2OH group; Section 18-12).
The solubilized bilirubin is excreted from the liver in bile, which flows into the
small intestine. Here the bilirubin diglucuronide is changed, in a multistep
process, to either stercobilin for excretion in feces or urobilin for excretion in
urine. Intestinal bacteria are primarily responsible for the changes that produce
stercobilin and urobilin. ▼
Bile Pigments
 The tetrapyrrole degradation products obtained from heme are known as
bile pigments because they are secreted with the bile, and most of them
are highly colored. A bile pigment is a colored tetrapyrrole degradation
product present in bile.
Biliverdin and bilirubin
 are, respectively, green and reddish orange in color.
Stercobilin
 has a brownish hue and is the compound that gives feces their
characteristic color.
Urobilin
 is the pigment that gives urine its characteristic yellow color.
Normally, the body excretes 1–2 mg of bile pigments in urine daily and 250–
350 mg of bile pigments in feces daily. When the body is functioning properly,
the degradation of heme in the spleen to bilirubin and the removal of bilirubin
from the blood by the liver balance each other.
Jaundice
 is the condition that occurs when this balance is upset such that bilirubin
concentrations in the blood become higher than normal.
 The skin and the white of the eyes acquire a yellowish tint because of the
excess bilirubin in the blood.
 Jaundice can occur as a result of liver diseases, such as infectious hepatitis
and cirrhosis, that decrease the liver’s ability to process bilirubin; from
spleen malfunction, in which heme is degraded more rapidly than it can be
absorbed by the liver; and from gallbladder malfunction, usually from an
obstruction of the bile duct.
 The local coloration associated with a deep bruise is also related to the
pigmentation associated with heme, biliverdin, and bilirubin. The changing
color of the bruise as it heals reflects the dominant degradation product
present as the tissue repairs itself.
Metabolism of Hemoglobin - Abian, Elaine P.
It is basically the breakdown of hemoglobin into metabolites: heme, globin,
bilirubin, biliverdin,
and iron.
● Red Blood Cells
- A non nucleated molecule and is mainly composed of approximately 270 million
hemoglobin molecules, a globular protein.
- It undergoes the process of hemolysis where it is continuously being broken
down
mainly in the spleen but some are in the liver. About 100-200 million are being
broken down each hour
- Has a lifespan of 120 days.
● Hemoglobin
- A tetramer, has four polypeptide chains, that contains four heme groups that
allows the hemoglobin to travel 4 oxygen molecules all at the same time, and a
globin peptide.
- Globin peptides have 2 alpha chains and 2 beta chains. They are linked
together to
form a compact and stable structure for efficient oxygen binding and release.
● Spleen
- Has a red pulp that contains the splenic cords or the Cords of Billroth where
reticular fibers are found.
- Reticular fibers have very narrow passageways so red blood cells must fold to
be
able to pass.
- Old or senescent red blood cells lose their folding ability resulting in rupture in
the Cords of Billroth.
● Reticulo-Endothelial System
- Network of cell tissues primarily composed of phagocytic cells like
macrophages
and monocytes. It plays an important role in clearing out old and abnormal cells.-
Breaks down the hemoglobin into globin and heme wherein globins are broken
down into free amino acids and are later used to produce proteins.
- Leftover hemes will be degraded since they are toxic.
● Heme
- Composed of a porphyrin ring, composed of 4 pyrrole rings, and an iron at the
center that is actually the one who binds to the oxygen.
● Heme synthesis
1. In the mitochondria, Succinyl CoA combines with Glycine through ALA
Synthase, an enzyme that catalyzes the first step, and produces delta
aminolevulinic acid.
2. Through ALA Dehydratase, two molecules of delta aminolevulinic acid will go
to
the cytoplasm and release two water molecules and produce Porphobilinogen.
3. It will be converted into Uroporphobilinogen I when four Porphobilinogen
molecules forms a linear tetrapyrrole through synthase, it is non-enzymatic so
the
cycle is slow and the pattern would be AP, AP, AP, AP (A- acetic acid and
Ppropionic acid).
4. When Cosynthase is added the linear tetrapyrrole will speed up the reaction
and
therefore forming a Uroporphobilinogen III wherein the structure of substituents
are AP, AP, AP, PA.
5. Uroporphobilinogen III will be converted into Coproporphyrinogen III when
acetic acid groups decarboxylates and converts them to methyl group.
6. By converting the propionic acid groups of rings I and III to vinyl group,
Coproporphyrinogen III will be Protoporphyrinogen IX through oxidation back to
the mitochondria.
7. When Protoporphyrinogen IX is oxidized it will be converted into
Protoporphyrin
IX and when it combines with an Iron, through Ferrochelatase, it will form a
heme.
8. When a heme combines with a globin it will form a hemoglobin.
● Hemoglobin Breakdown
1. Heme will be converted into Biliverdin, a pigmented green molecule, through
heme oxygenase wherein O2 and NADPH are needed in this process and CO2
will be released when we exhale.
2. Biliverdin will be converted into Bilirubin, a pigmented orange molecule,
NADPH is again needed in this process as well as the Hydrogen+. This process of
converting Biliverdin to unconjugated Bilirubin is what happens during the color
changing of the bruise due to the breakdown of red blood cells.
3. Unconjugated Bilirubin is lipophilic therefore it needs to bind to Albumin, the
most abundant serum protein that acts as protective mechanism that prevents
entry of bilirubin into tissues because it can be toxic cells.
4. When an albumin and unconjugated bilirubin binds together, the transport to
the
blood will be easier. The albumin will drop off the bilirubin to the liver where
most enzymatic conversion happens.
5. The unconjugated Bilirubin will be conjugated into UDP Glucuronide through
an
enzyme called UDP-Glucuronyl Transferase 1&2 making the bilirubin more
soluble in water and more efficient to be excreted into the urine and feces.
6. Conjugated bilirubin will be released in the bile within the gallbladder and
when
the gallbladder releases the bile into the small intestine, the bilirubin will also be
released.
7. Small intestines have numerous intestinal bacteria in it and when this
unconjugated bilirubin interacted with it, it will be oxidized and be converted into
urobilinogen.
8. Still in the small intestine, urobilinogen will be further processed by intestinal
bacteria and be converted into stercobilin which is brown in color and will be
excreted into the feces. Explaining why feces are brown in color.
9. Some urobilinogen will go back to the bloodstream and be transported in the
kidney. These urobilinogen will be converted into urobilin, yellow in color, and
will be excreted into the urine, therefore giving the urine its yellow color.
● Urobilinogen in Urine
- Urobilinogen levels in urine can determine the body’s bilirubin metabolism,
usually measured in milligrams per deciliter.
Normal Range (0.2 mg/dL)
- No disease associated.
Slightly Elevated (1 mg/dL)
- Within normal range but is advisable to further investigate for medical
conditions.
Elevated (2-4 mg/dL)
- Could be increased of bilirubin production or impaired liver function and
may be seen in liver diseases like hepatitis, cirrhosis, or conditions related
to increased red blood cells breakdown.
Significantly Elevated (8 mg/dL)
- Associated with severe condition. Could be advanced liver disease, acute
hepatitis, or extensinve hemolysis.