Download 26.7 Defects of omino ocid metobolism 26,8 Hemoglobin ond bile

26.8 Hemoglobinand Bile Pigments
799
26.7 Defectsof omino ocid metobolism
AIM: To describethe couse,effects,ond treotmentof
phenylketonurio.
Focus
There are manyknown defects
of amino acid degradation.
Since there are a large number of amino acids, the possibilities for diseases
related to amino acid metabolism are also great.Many of the diseasescaused
by defects of amino acid metabolism are rare. The most common are the
amino acidurias-conditions inwhich amino acidsor relatedcompoundsare
excretedin large quantities in the urine. One example of an amino aciduria is
phenylketonuria, which occurs about once for every 10,000births.
Phenylketonuria (PIru) is the result of an inborn error of metabolism in
which phenylalanine hydroxylase,the enzymeresponsiblefor the conuersion
of phenylalanine to tyrosine,is inactiue.This conversion is necessaryfor the
complete catabolism of the benzenering of phenylalanine.Sincephenylalanine cannot be degraded further without being converted to tyrosine,
the levels of phenylalanine and its deamination product, phenylpyruvic
acid, build up until they are excretedin the urine in large quantities.
Phenylalanine
In the inherited diseaseiminoglycinuria, the urine contains
excessiveamounts of proline,
hydroxyproline, and glycine.
Phenylpyruvic acid
Left untreated, phenylketonuria results in severemental retardation by
age6 months. lVhy retardation occurs is not kno'orn,but it can be prevented
or greatly alleviated by feeding the newborn infant a diet low in phenylalanine. (Phenylalanine cannot be eliminated from the diet entirely becauseit
is an essentialamino acid.) Since the retardation due to phenylketonuria
can be preventedbut not reversed,many statesrequire the routine screening of urine samplesof all newborn infants for signs of the disease.One
screeningtest is very simple.Addition of a few drops of a dilute solution of
ferric chloride to a small urine sample gives an olive-green color if the baby
has phenylketonuria. The color results from a complex formed by ferric
ions and phenylpyruvic acid. A Closer Look The Amino Acidurias examines
other defects of amino acid metabolism.
26,8Hemoglobinond bile pigmenfs
AIMS: To troce the degrodationof hemoglobin,indicoting two
importont resultsof the process.To list somepossihle
cousesof joundice.
Heme groups of hemoglobin
are degraded to the bile
pigment bilirubin.
Hemoglobin is synthesizedby means of many complex reactions that take
place in immature red blood cells.In the mature red blood cells,the hemoglobin doesits work by transporting oxygento body tissues.The life span of
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26 Metabolismof NitrogenCompounds
CHAPTER
TheAmino Acid,urias
Phenylketonuria is only one of many amino
acidurias that are recorded in the medical literature (seefigure).All are the resultof inborn errors
of metabolism. Alkaptonuria is a disease related
to the inability to break dovrn phenylalanine, although the error in the catabolism of the phenylalanine is different from that in phenvlketonuria.
In phenylketonuria, as we have mentioned, the
body lacksthe enzymenecessaryto put a phenolic
hydroxyl group on the benzene ring ofphenylalanine in order to make tyrosine. Alkaptonuria is a
diseaseof tyrosine metabolism. In alkaptonuria, the
conversion of phenylalanine totposine occurs,but
an enzyme necessalyto degradethe benzene ring
of tyrosine is lacking or defective. Ingested ty'rosinein the body is incompletelyconvertedinto its
normal degradation products, and the partially
degradedproducts are excretedin the urine. These
products are colorless when excreted but soon
form a dark red pigment when exposedto air. The
urine of people who have alkaptonuria may be
colored from wine red to black depending on the
concentration of the pigment. The pigment also
forms in the bones,connectivetissue,and organs
of alkaptonuric patients. This deposition is
thought to be the cause of arthritis that develops
in many individuals with alkaptonuria. Except for
the discomfort of arthritis, many alkaptonuric
individuals have lived long and reasonablyhealthy
lives.
Thebloodof newborninfantsis routinelyscreened
for
(PKU).
phenylketonuria
An interestinggroup of amino aciduriasis the
family of diseasesgrouped as the maple syrup
urine diseases.Many genetic diseases are found
mainly in families and small groups that are
highly intermarried.Maple spup urine diseaseis
a thousand tirnes more common among the Old
Order Mennonites of Pennsylvania than in the
general population. The genetic flaws in the
maple s1'rupurine diseasesare in the catabolism
of the branched-chainamino acids such as
leucine and valine.The excretionof the products
of incomplete breakdor,rmof branched-chain
amino acids imparts the odor of maple s1'rup to
the urine. The product or products that give the
urine this characteristic odor are unknown. Many
individuals with maple syrup urine diseaseare
mentally retarded and generally have short life
spans.
the averagered blood cell is about 120 days.The spleen-an organ of the
l1'rnphaticsystem-fllters out cells that have reached the end of their useful
lives.In the spleen,red blood cell membranesare broken do'ornand hemoglobin spills out. Globin, the protein portion of hemoglobin, is hydrolyzed
to its individual amino acids.
Degradationof heme begins with the removal of a single carbon from
the heme ring by an oxidation reaction (Fig.26.5).Theproduct of oxidation
of heme is biliverdin, a green pigment. The iron releasedwhen heme is oxidized to biliuerdin is retained in the body as a complex with the proteinferritin. Reduction conuertsbiliuerdin ro bilirubin, an orange-redpigment.
Bilirubin entersthe circulation and is transportedto the liver as a complex
with serum albumin. From the liver it moves to the gallbladder, where it is
26.8 Hemoglobinand Bile Pigments
H:Cr
/C:CH2
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t.--L
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ll \
,o,r.t,.rll-
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HO2CCH2CH2
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Bilirubin
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HO2CCH2CH2
.,Lo,
CH'
Figure26.5
(a) releases
to the bilepigmentsbiliverdin
Hemoglobin
hemewhichis degraded
(b) andbilirubin(c).
stored as part of the bile and eventually excreted into the small intestine
along with the bile salts.
An excessof bilirubin in circulating blood is responsible for iaundiceayellow color of the skin and the whites of the eyes.laundiceis causedby any
of a number of malfunctions of the bile production and storagesystem (see
A Closer Look Hyperbilirubinemia). If the bile duct is obstructed, the bile
enters the circulation rather than the small intestine. The obstruction mav
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26 Metabolismof NitrogenCompounds
CHAPTER
be due to gallstones,which often consistof nearlypure cholesterol.\Altrythe
cholesterolforms these hard, insoluble lumps in the gallbladdersof some
people and not in others is still not understood.In certain diseases
such as
infectious hepatitis, the liuer cannot remoue bile pigments as they are
formed, and they enter the circulation. Hemolytic jaundice occurs when
breakdown of heme groups by the spleen is faster than the liuer can remoue
the bile that is produced.
Bilirubin that passesfrom the small intestine into the large intestine is
oxidized to colorlessurobilinogen by bacteria residing there. The urobilinogen oxidizes in air to orange-yelloruurobilin. The excreted urobilin gives
fecestheir color.The yellow color of urine is the result of a small amount of
urobilin filtered from the bloodstreamby the kidneys.
Hyperbilirubinemia
Before birth, biliverdin (from the breakdown of
fetal hemoglobin) is converted to bilirubin and
crossesthe placenta into the mother's liver. It is
then secretedin her bile. At birth an infantls liver
must take over this vital function: to do this. the
liver cells must be mature. Usually the iiver
becomes fully functional within the first week
after birth. But if it doesnot, high serum bilirubin
Ievels accumulated in the blood (hyperbilirubinemia) and skin (jaundice) cause the infant's
skin to turn yellow If the maturation period of
the liver is prolonged,bilirubin may startto accumulate in brain tissue.Left untreated, this condition can lead to cerebralpalsy,brain damage,and
death.
Phototherapy(seeA CloserLook: Phototherapies, on page 706) is used to treat hlperbilirubinemia. V\4renbilirubin is exposed to white fluorescent light or sunlight, it is convert edto photobilirubin. Therefore, if an infant suffering from
hyperbilirubinemia is exposed to fluorescent
light, some of the bilirubin in blood flowing near
the skin is converted to photobilirubin. Photobilirubin is more water-soluble than bilirubin
because of a slight difference in molecular structure. Becausethis photoproduct is more soluble in
water than in fatty tissues, it leaves the skin and
enters the blood circr.rlation.From the blood it
passesto the liver and is readily secretedin bile
and excretedin the urine and feces.
During phototherapy, lnfants may be exposed
to florescentlight (seefigure)for periodsof B to l0
hours daily for a week or until the liver cells reach
maturity. The infant's eyes are covered to prevent
possibledamage.He or she is fed intravenouslyto
minimize dehydration and turned frequently;
only the skin exposed to light losesits yellow color
as the bilirubin is changed to photobilirubin and
excreted.
lnfant undergoingphototherapyfor
hyperbilirubinemia.
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