Lecture 8 by Prof.Dr.Munaf Salih Daoud
Alcohol metabolism,Biochemical lesion
of CHO metabolism in RBCs &
Aminosugars metabolism
Objectives
:1-Describe Ethanol & Methanol
Metabolism.
2- State why both are harmful to the body &
how treated ( Toxicity )
3- List the factors that damage RBCs causing
Hemolysis.
4- Simple description of Aminosugars
metabolism & their intercoversion and
the importance of these sugar
derivatives.
Ethanol Metabolism
* Ethanol (CHɜCH
2
OH ) may replace CHO
as energy source when ingested 1gm →9
calories energy
* oxidized with NAD+ in liver by
cytosolic Alcohol dh. to acetaldehyde
CH
3
CHO & NADH
.
Further oxidation by mitochondrial
Aldehyde dh. give acetate & NADH.
* Much of the acetate leaves the liver to
other tissues & with CoASH converts to
Acetyl CoA ( active Acetate )which is a CAC
( Kerb̕s cycle) substrate i.e. oxidized to CO
2
& H
2
O.
Or Acetyl CoA formed in the liver & used as
a precursor for fatty acid synthesis & then
lipid synthesis ( Lipogenesis
)
Or Ethanol may also be oxidized by
microsomal cytochrome P450
oxidase(induced by ethanol).
*
Chronic ethanol ingestion can cause
Fatty liver disease (FLD)or
Hepatosteatosis . This is due to an
imbalance between hepatic
TAG(TG)synthesis & secretion of VLDL .
Other Clinical conditions that cause FDA
are acute hepatitis & uncontrolled DM.
* Ethanol can not be synthesized in
human body but in microorganism (
yeast ) Pyruvate with TPP &
decarboxylase(CO
2
removal ) to
converts to Acetaldehyde that is
reduced with NADH to Ethanol.
* Biomedical importance
:
It causes 1- Cirrhosis 2- Reactive (
functional) hypoglycemia or Alcohol -
induced hypoglycemia.
Hypoglycemia may develop between
2-10 hrs after ingestion of large
amounts of alcohol & found most
often in malnourished persons &
chronic alcoholics , but may occur in
young persons when they first drink
alcohol .It causes suppression of
Gluconeogenesis during its
metabolism .HOW ?
In liver NADH/NAD+ ratio is high
due to Ethanol metabolism.
Pyruvate destined for
gluconeogenesis is shunted to
lactate in order to regenerate
NAD+
to allow alcohol
metabolism to continue . Similarly
oxaloacetate is shunted to
malate(also to regenerate )
NAD.
+
Dihydroxyacetone phosphate (DHAP)
coming from lipid breakdown , Lipolysis ,
through Glycerol→Glycerol3-P→DHAP
is shunted to form
NAD
Treatment
: Disulfiram(an Antidote)
drug used for chronic alcoholism).It
inhibits Aldehyde dh.by competing
with
NAD
for binding site of this
enzyme & so ↑↑acetaldehyde level in
blood causing symptoms of vomiting,
+
+
Thirst,sweat& headache.
* Methanol ( CHɜOH)
. May be ingested by mistake
. Oxidized with NAD+ by liver alcohol
dh. to formaldehyde
(HCHO
)which is oxidized by Ald.dh.to
formic acid(formate)HCOOH.
Toxicity:*
Formaldehyde causes retinal
damage&blindness.Formic acid causes
Acidosis,Coma & Death.
Treatment:
An antidote ethanol is given
which is a competitive inhibitor of the
dehydrogenase enzymes causing a delay of
methanol metabolism & its increased
excretion in urine.
. in
Metabol
Biochemical Lesion of CHO
RBCs
RBCs are synthesized in bone marrow &
have a life span of 120
days(4months)i.e.half life 60 days.
* Mature RBC(lack mitochondria) &
hence utilize the Anaerobic glycolysis to
provide energy(ATP)& 2,3,-bisPG which
play a role in the delivery of O
2
to
tissues.It also use PPP(HMP shunt) for
NADPH which maintain SH group of the
Amino acid Cysteine in the tripeptide
Glutathione & the SH-containing
proteins in the reduced form(e.g.
glycolytic enzyme Glyceraldehyde 3-P dh
and membrane proteins
=
Erythropoietin ( EPO)
Hemopoietin=Hematopoietin
: a glycoprotein
hormone that controls RBCs ,
production) ,
mainly produced in kidney & less in liver then
released into the blood to act as RBCs
precursors in bone marrow.
*1- Certain drugs cause a decrease in the
number of circulating RBCs ( impaired
production) as in Bone Marrow Aplasia due to
treatment with chloramphenicol .Recombinant
human EPO(rHuEPO)is used in treatment of
patients with Renal failure on Hemodialysis.
2- A variety of chemicals causes a
destruction of RBCs
membranes(hemolysis)…How?
:
Several factors contribute
1- by oxidation of the SH group of
a- cell membrane proteins
b- the enzyme Glyceraldehyde
3-P dh.
2- Biochemical lesions in the synthesis
of Glutathione-reduced form (GSH).
Glu-Cys-Gly
ɪ
SH
i.e. should not be in the oxidized form (
GSSG)
Glu-Cys-Gly
ɪ
S
ɪ
S
3- Lack of the enzyme Glutathione
peroxidase.
4- Vitamin B
2
(flavoprotein)
deficiency affect Glutathione
Reductase.
5-Glucose 6-P dh. Deficieny
affecting NADPH production(i.e. the
or HMP shunt . NADPH
reduces GSSG to GSH.
PPP
1- Glc-6P+NADP → 6-Pgluconic
acid+ NADPH by
Glc6Pdh(G6PD)
2- NADPH + GSSG →NAD +
GSH
by
Glutathione Reductase
3- GSH + H
2
O
2
→ GSSG +
H
2
O by
Glutathione Peroxidase
Glutathione ( an Antioxidant) &
NADPH maintains the integrity of SH
group in enzymes,Hb,cell membrane
proteins
If the enzymes in 1,2,3 are not
present or deficient then H
2
O
2
will
accumulate inside the RBCs causing
oxidation of their cell membranes.
6- Glc6-P deficiency is an inherited sex-
linked factor of inborn error of
metabolism. Some drugs, chemicals or
type of food affect some people & may
cause Hemolytic Anemia . These are:
a- Anti-malarial drug – primaquine.
b- Sulfonamide& sulfones.
c- Analgesics- acetaniline.
d- Antibacterial- nitrofuragon.
e- Ingestion of vicia fava bean.
f - Nephthaline.
g - Phenylhydrazine.
7- Hemoglobin shifting of equilibrium
between HbO
2
& MetHb due to :
a- Drugs like sulfonamides(
bacteriostatic drugs).
b - Lack of Glyceraldehyde 3-P
dh.(glycolytic enzyme).
c- Decreases of NADH causes
increases of MetHb(NADH is required to
convert it into HbO
2
by the enzyme
MetHb reductase).
d- Lack of the enzyme Glutathione
peroxidase.
Increased level of MetHb is known as
Methemoglobulinemia
& is associated
with Hypoxia which causes Cyanosis &
increased Respiratory rate.
[ NB. HbO
2
-oxyhemoglobin- oxygenated
Hb,Iron is in its reduced form i.e.ferrous
ion Fe
2+
, can carry oxygen .
MetHb- methemoglobin ( non
oxygenated), iron is in its oxidized
form i.e. ferric ion Fe ɜ+ , can not
carry oxygen , it is brown in color & is
normally present in very low blood
.
concentration
Metabolism of Aminosugars
:
Aminosugars
Glucosamine,Mannosamine,Galactos -
their derivatives.
&
amine
Glucosamine6-Phosphate(GlcN6-P)
*
is the precursor of All hexoseamine
in glycosaminoglycans
residues
( mucopolysaccharides)
.
*Sources of it is glycogen , glucose &
AA metabolism and its precursor is
Glc6P which converts into it by
amidination
or diet glucosamine that
is phosphorylated by ATP.
*
GlcN6P
convert to
GlcN1P
to be
activated by
UTP
to form
UDP-GlcN
that
conjugates
with
glucuronic acid
to give
Heparin
of blood.
*
GlcN6P
gets
acetylated
by
Acetyl CoA
to convert into
GlcNAc6P
& then
GlcNAc1P
to be activated by UTP to
form
UDP-GlcNAc
or
UDPGalNAc
both
to be
conjugated
with glucuronic acid to
give
Hyaluronic acid
( found in
Eye,Synovial fluid & Placenta) and
Chondroitin Sulfate(found in
Cartilage),respectively.
*
GlcNAc6P
can convert to
ManNAc6P
to be combined with
pyruvate to form
NANA9-P
(Sialic
acid) ( found in gangliosides & Rh-
factor glycoprotein.
Summary:
1-Ethanol act as energy supplier
through formation of Active acetate,
Acetyl CoA. But it is detrimental
substance that cause Fatty Liver
Disease(FLD)
or Hepatosteatosis,Cirrhosis and
also Hypoglycemia
2- Methanol ingested by mistake ,is a
toxic ,fatal substance.
3- RBCs are maintained by Glutathione (
an Antioxidant) & Enzymes &
Coenzymes involved in the prevention
of H
2
O
2
accumulation ( Peroxidation)
namely G6PD, glutathione reductase &
peroxidase and NADPH.
4- RBCs production is affected by bone
marrow,kidney & liver diseases through
Its Erythropoietic factor the
Erythropoietin and by certain drugs.
5- G6PD deficiency & certain
substances ,drugs,chemicals,fava
bean…etc can cause Hemolytic
Anemia.
6- Aminosugars form the structures of
different glycosaminoglycans found in
eye,synovial fluid,cartilage,blood
anticoagulant,Rh-factor…etc.