Transcript Overview of metabolism

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Aerobic Oxidation of Glucose:
(Oxidative Decarboxylation
of Pyruvate & Krebs' Cycle)
After the conversion of glucose into two
moles of pyruvate through the glycolysis,
pyruvate is oxidatively decarboxylated into
Acetyl-CoA in the mitochondria by the
pyruvate dehydrogenase enzyme complex.
Krebs' Cycle
= Citric acid cycle
= Tricarboxylic acid cycle (TCA)
1. Formation of citrate
2. Formation of Isocitrate via cis-Aconitate
3. Oxidation of Isocitrate to α-Ketoglutarate and CO2
4. Oxidation of Isocitrate to α-Ketoglutarate and CO2
5. Conversion of Succinyl-CoA to Succinate
6. Oxidation of Succinate to Fumarate
7. Hydration of Fumarate to Malate
8. Oxidation of Malate to Oxaloacetate
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Biological importance of Krebs'
cycle
Bioenergetics of Krebs' cycle
Oxidative decarboxylation of the two mole of
pyruvate produced from one mole of glucose
gives 2 NADH.H+ that gives  6 ATP.
Oxidation of isocitrate by isocitrate
dehydrogenase gives 2 NADH.H+ that gives  6
ATP.
Oxidative decarboxylation of -ketoglutarate to
succinyl-CoA gives 2 NADH.H+ that gives  6
ATP.
Substrate level phosphorylation from succinyl-CoA
gives  2 ATP.
Oxidation of succinate to fumarate gives 2 FADH2,
thus  4 ATP.
Oxidation of malate to oxaloacetate gives 2 NADH.H+,
i.e., 6 ATP.
Thus, for each mole of glucose oxidized by oxidative
decarboxylation followed by Krebs' cycle 30 ATP are
produced.
Complete oxidation of one glucose molecule in
aerobic conditions gives 8 ATP at aerobic glycolysis +
30 ATP at Krebs' cycle giving a total of 38 ATP.
Regulation occurs at the following
sites:
Citrate synthase:
it is an allosteric enzyme inhibited by ATP and
long chain fatty acyl-CoA. It is competitively
inhibited by succinyl-CoA.
Isocitrate dehydrogenase:
The enzyme is allosterically activated by ADP
and NAD and inhibited by ATP and NADH.H+.
-Ketoglutarate dehydrogenase:
The enzyme is regulated by phosphorylation
/dephosphorylation mechanism in a manner
similar to pyruvate dehydrogenase. This
enzyme is inhibited by accumulation of ATP,
succinyl-CoA and NADH.H+.
Succinate dehydrogenase
It is inhibited by oxaloacetate and malonate.
That depends on the NADH/NAD ratio.
Inhibitors of Krebs' cycle:
Fluoroacetate: This compound in the form of
fluoroacetyl-CoA condenses with oxaloacetate
to form fluorocitrate that inhibits aconitase
leading to accumulation of citrate.
Arsenate: inhibits both pyruvate dehydrogenase
and -ketoglutarate dehydrogenase.
Malonate or oxaloacetate: Inhibits succinate
dehydrogenase enzyme (competitive inhibition).
Mercury inhibits succinate dehydrogenase.
Sources and fates of oxaloacetate
A - Sources:
1. Carboxylation of pyruvate.
2. Oxidation of malate.
3. Cleavage of citrate.
4. Transamination of aspartate.
B - Fates:
1. Reduction into malate.
2. Synthesis of citrate .
3. Transamination into aspartate.
4. Conversion into phosphoenolpyruvate.
Hexose Monophosphate Pathway
(HMP)
(Or, Pentose Shunt)
Definition:
It is an alternative minor pathway for glucose
oxidation that does not produce ATP nor utilize it.
It aims at producing NADPH+H+ and ribose.
It is considered as a shunt from the main stream of
glycolysis.
Intracellular site and tissue distribution:
It is cytosolic in tissues characterized by active fatty
acid or steroid synthesis namely: liver, adipose tissues,
lactating mammary gland, RBCs, suprarenal cortex,
thyroid and testis.
It is not active in non-lactating mammary gland, and
in skeletal muscles.
Regulation of HMP shunt: The key regulatory enzymes are glucose-6phosphate and 6-phospho-gluconate
dehydrogenases.
They are activated by fed state, glucose, insulin,
thyroxine and NADP but are inhibited during
starvation, diabetes mellitus and with high
NADPH.H+/NADP ratio.
Functions and metabolic
importance of HMP shunt:
I- Production of pentoses:
Tissues must satisfy their own requirement of
pentoses since dietary pentoses are not utilizable and
ribose is not a significant constituent of systemic
blood.
Pentoses are used for:
1. Nucleic acids, ribose for RNA and deoxyribose for
DNA.
2. Coenzymes synthesis, e.g., NAD, FAD, CoASH.
3. Other free nucleotide Coenzymes, e.g., ATP, GTP,
4. Synthesis of certain vitamins, e.g., B2 and B12.
II- Production of NADPH.H+
Tissues having the following metabolic and
synthetic pathways have active HMP shunt
(liver, adipose tissue, lactating mammary gland,
kidney, testis, ovary and adrenal cortex).
HMP pathway is the major human source for
production of NADPH.H+ required for:
1. Fatty acid synthesis (lipogenesis) and fatty acid
desaturation.
2. Cholesterol synthesis.
3. Other steroid synthesis.
4. Synthesis of sphingosine and cerebrosides.
5. Synthesis of non-essential amino acids, e.g.,
glutamate (through the reversible glutamate
dehydrogenase) and tyrosine from phenylalanine.
6. Regeneration of reduced glutathione.
7. Metabolic hydroxylation with cytp450.
Favism
Glucose-6-phosphate dehydrogenase deficiency
(sometimes also called G6PD deficiency, or favism) is
a hereditary disease.
As it is linked to the X chromosome, most people who
suffer from it are male.
Sufferers can not make the enzyme glucose-6phosphate dehydrogenase.
This will mean the circulation of sugar in their body is
different.
G6PD catalyzes the first step in the pentose
phosphate pathway, which produces NADPH.
This reductant, essential in many biosynthetic
pathways, also protects cells from oxidative
damage by hydrogen peroxide (H2O2) and
superoxide free radicals, highly reactive
oxidants generated as metabolic byproducts
and through the actions of drugs such as
primaquine and natural products such as
divicine—the toxic ingredient of fava beans.
During normal detoxification, H2O2 is converted to
H2O by reduced glutathione and glutathione
peroxidase, and the oxidized glutathione is converted
back to the reduced form by glutathione reductase
and NADPH.
H2O2 is also broken down to H2O and O2 by catalase,
which also requires NADPH.
In G6PD-deficient individuals, the NADPH production
is diminished and detoxification of H2O2 is inhibited.
Cellular damage results: lipid peroxidation leading to
breakdown of erythrocyte membranes and oxidation
of proteins and DNA.
An antimalarial drug such as primaquine is believed
to act by causing oxidative stress to the parasite.
It is ironic that antimalarial drugs can cause illness
through the same biochemical mechanism that
provides resistance to malaria.
Divicine also acts as an antimalarial drug, and
ingestion of fava beans may protect against malaria.
Uronic acid Pathway
It is another minor alternative pathway for
glucose oxidation by which glucuronic acid,
ascorbic acid and pentoses are obtained from
glucose.
Like HMP shunt, it does not need nor generate
ATP.
Site:
In cytosol of many tissues, especially liver,
kidney and intestine.
Biological importance of Uronic Acid Pathway:
1-Production of UDP-glucuronic acid, which is the
metabolically active form of glucuronic acid which
enters in:
• Synthesis of mucopolysaccharides.
• Detoxification by conjugation: UDP-glucuronic acid is
used to detoxify steroid hormones, drugs and toxins.
• Formation of conjugated bilirubin.
2-Formation of pentoses.
3-Formation of vitamin C in plants and animal except
man and guinea pigs.
Thank You
Edited by
Dr/Ali H. El-Far
Lecturer of Biochemistry
Fac. of Vet. Med.
Damanhour Univ.