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Department of Biochemistry
Learning Objectives
? Fates of Amino Acids
? Sources of Amino Acids
? Amino Acid Utilization
? Nitrogen Balance
? Amino-group metabolism
? Transamination
? Deamination
? Transdeamination
? Transamidation
? Decarboxylation
? Transmethylation
Role of Glutathione in Amino Acid Absorption
? Meister proposed that glutathione participates in an active
group translocation of L-amino acids (except L-Pro) into cells of
small intestine, kidneys, seminal vesicles, and brain.
? He proposed a "cyclic" pathway/-glutamyl cycle in which
Glutathione is regenerated again
? -glutamyl transferases (GGT) plays a key role in this cycle, a
pathway for synthesis and degradation of glutathione and drug
and xenobiotic detoxification
-glutamyl/Meister cycle
Fig.26.1: Text Book of Medical Biochemistry by Chatterjee & Rana Shinde, 8th Ed
Disorder related to aa transporter
Hartnup disease: Defect in SCL6A19 gene, it is a sodium-
dependent and chloride independent neutral aa transporter,
expressed in kidneys and intestine
? This gene controls the absorption of certain aa from intestine
and reabsorption of those aa in kidneys
? Person with Hartnup disease cannot absorb aa properly from
intestine and cannot reabsorb them from tubules in kidneys
Cont--
? Resulting excessive amount of aa such as Trp excreted in urine
? Due to inadequate amount of Trp, body not able to make sufficient
amount of niacin (vit B3), which is necessary component of NAD+
? Pellagra, a similar condition, is also caused by low nicotinamide; this
disorder results in dermatitis, diarrhea, and dementia
Cont--
? Cystinuria: Dibasic (diamino aa) transporter Lys, Arg, Ornithine
and Cys. If there is any defect in this transport system, it leads
to Cystinuria
? In medicine, Garrod's tetrad is a term named for British
physician Archibald Garrod, who introduced the phrase "inborn
errors of metabolism" in a lecture in 1908
? Tetrad comprises four inherited metabolic diseases: albinism,
alkaptonuria, Cystinuria and pentosuria
Fates of Amino Acids
? For Protein synthesis
? For synthesis of other nitrogen containing compounds (heme,
creatine, purines, pyrimidines, choline, neurotransmitters)
? For the gluconeogenesis
? Energy source from glucogenic aa and ketogenic aa
Glucogenic aa: Give rise to a net production of pyruvate or TCA
cycle intermediates, such as -ketoglutarate , succinyl CoA,
Fumarate and oxaloacetate, all of which are precursors to
glucose via gluconeogenesis. Ex. Ala & Arg
Cont--
Ketogenic aa: Lysine and leucine are the only aa are ketogenic,
giving rise only to acetylCoA or acetoacetylCoA, neither of which
can bring about net glucose production. Ex. Leu and Lys
Glucogenic and Ketogenic aa: Small group of aa comprised of
Ile, Phe, Thr, Trp, and Tyr give rise to both glucose and fatty acid
precursors and characterized as glucogenic and ketogenic
Sources of Amino Acids
? Ingested dietary proteins is hydrolysed to aa and absorbed from
the intestine
? Breakdown of tissue/body proteins
? Glycolysis and citric acid cycle
? Synthesis of non-essential aa
Amino Acid Utilization
Degradation of an aa in two
stages:
a) Carbon skeleton, is then converted to
pyruvate, acetyl CoA, or citric acid cycle
intermediate, depending on its makeup,
with the resulting energy production or
energy storage
b) Amino nitrogen atom is removed and
converted to ammonium ion, which
ultimately is excreted from the body as
urea.
Nitrogen Balance
Nitrogen balance occurs when synthesis of body protein equals
degradation.
? Amount of nitrogen excreted in the urine each day equals the
amount of nitrogen ingested each day
Positive nitrogen balance occurs when synthesis of body protein
excess compare to degradation.
? Less nitrogen is excreted than ingested (growth, e.g. growing
infants and children, pregnant women, tissue repair)
Cont--
Negative nitrogen balance occurs when synthesis of body protein
lesser compare to degradation.
? More nitrogen is excreted than ingested (malnutrition, absence
of one or more essential aa in diet)
? It occurs in injury, stress response, malnutrition of essential aa
Amino-group metabolism
? -amino group is the nitrogen source during aa
metabolism
? Nitrogen is removed from aa as a ammonia,
which needs to be detoxified to urea
Three steps involved in flow of nitrogen from aa to
urea:
(1) Transamination (amino group transferred to
glutamate),
(2) Oxidative deamination of glutamate (removal of
amino group),
(3) Synthesis of Urea
Fig 19.15. Lippincott's Illustrated Reviews, Biochemistry, 6th Ed
Transamination
? -NH2 group of one aa is transferred
to a -ketoacid resulting in formation
of a new aa and a new ketoacid
? Donor aa (I) becomes a new
ketoacid (I) after losing the -NH2
group, and recipient ketoacid (II)
becomes a new aa (II) after
receiving the NH2 group
Text Book of Medical Biochemistry by Chatterjee & Rana Shinde, 8th Ed
Cont--
? -amino group from L-amino acid is
transferred to -carbon atom of -
ketoglutarate, produced -keto acid and
glutamate
? Transfer of amino groups from one carbon
skeleton to another is catalyzed by
aminotransferases
? Al aminotransferases have prosthetic group,
which is pyridoxal phosphate (PLP),
coenzyme form of pyridoxine or vitamin B
Fig18.4: Lehninger Principles of Biochemistry by David L Nelson
6
Cont--
? Transfer of an -amino group from one aa to an
-keto acid in a reversible reaction
? Location: cytoplasm of all cells
? Enzyme: Transaminases (aminotransferases)
? Co-factor: Pyridoxal phosphate (PLP), derivative
of vitamin B6
? Common donor/acceptor pair: -ketoglutarate and
glutamate
Cont--
? Glutamate then functions as excretion pathways that lead to the
elimination of nitrogenous waste products
? Al aa except lysine and threonine participate in transamination
in their catabolism but they undergo deamination reaction
? Two aminotransferase reactions are catalyzed by alanine
aminotransferase (ALT ) and aspartate transferases (AST)
Cont--
Alanine aminotransferase
? In this alanine is the donor aa and -
ketoglutarate is the recipient ketoacid resulting
in formation of pyruvate and glutamate.
? During amino acid catabolism, this enzyme
functions in the direction of glutamate synthesis.
Aspartate aminotransferase
? In this Aspartic acid is the donor amino acid and
-ketoglutarate is the recipient ketoacid.
? During aa catabolism, this enzyme transfers
amino groups from glutamate to oxaloacetate,
forming aspartate, which is used as a source of
Fig 19.8. Lippincott's Illustrated Reviews, Biochemistry, 6th Ed
nitrogen in the urea cycle.
Diagnostic value of plasma aminotransferases
Alanine aminotransferase
? Normal enzyme activity is 3 to 15 IU/L
? It is entirely cytoplasmic
? Increases in viral hepatitis, diabetes, congestive heart failure, liver
damage
Aspartate aminotransferase
? Normal enzyme activity is 4 to 17 I.U/L
? It is cytoplasmic and also mitochondrial
? Increases in Liver diseases, muscular dystrophies, acute
pancreatitis, leukaemias, acute haemolytic anaemia
Deamination
? In oxidative deamination reactions result in the
liberation of the amino group as free ammonia
? Amino groups from many of the -aa are collected
in the liver in the form of the amino group of L-
glutamate molecules
? These amino groups must next be removed from
L-Glutamate semialdehyde
glutamate to prepare them for excretion
? In hepatocytes, glutamate is transported from the
cytosol into mitochondria, where it undergoes
oxidative deamination catalyzed by L-glutamate
Fig18.7: Lehninger Principles of Biochemistry by David L Nelson
dehydrogenase
Cont--
? It is the only enzyme that can use either NAD+ or NADP+ as the
acceptor of reducing equivalents
? This oxidative deamination of glutamate is the main mechanism for
release of aa nitrogen as ammonia (NH +) in a reversible reaction.
4
? Location: Mitochondria of hepatocytes
? Allosteric regulation of oxidative deamination: High energy state
inhibits the GDH and low energy state stimulates the enzyme.
Transdeamination
? Transfer of amino nitrogen to -ketoglutarate forms l-
glutamate.
? Hepatic l-glutamate dehydrogenase (GDH), which can use
either NAD+ or NADP+, releases this nitrogen as ammonia
? Conversion of -amino nitrogen to ammonia by the coordinated
action of glutamate aminotransferase and GDH is
"transdeamination"
Cont--
? Liver GDH activity is allosterically inhibited by ATP, GTP, and
NADH, and is activated by ADP
? GDH reaction is freely reversible, and also functions in aa
biosynthesis
? The -ketoglutarate formed from glutamate deamination can be
used in the citric acid cycle and for glucose synthesis
Transamidation
? Transamidation involves transfer of ?NH2 from a
carboxamide group to a suitable acceptor
? Formation of glucosamine-6-P:The amide-N of glutamine
can be transferred to a ketogroup
? If transferred to a Keto group of fructose-6-P, it forms
Glucosamine-6-P by a transamidation reaction from
Glutamine as the 1st step of hexosamine biosynthesis
pathway
Text Book of Medical Biochemistry by Chatterjee & Rana Shinde, 8th Ed
Decarboxylation
? Reaction by which CO2 is removed
from the COOH group of an aa as a
result an amine is formed
? This reaction is catalysed by
decarboxylase,
which
requires
pyridoxal-P (B6-PO4) as coenzyme
Text Book of Medical Biochemistry by Chatterjee & Rana Shinde, 8th Ed
? The enzyme removes CO2 from COOH
gr.
and
converts
the
aa
to
corresponding amine
Cont--
? End-product of this pathway is UDP-GlcNAc, used to make
glycosaminoglycans, proteoglycans and glycolipids
? The catalysing enzyme is L-glutamine-D-fructose-6-P
transamidase
Cont--
? This is mostly a process confined to putrefaction in intestines
and produces amines
? Ex. Threonine is converted into Propanol amine (Constituent of
Vit B12)
? Isoleucine undergoes transamination, followed by oxidative
decarboxylation of resulting -keto acid
Transmethylation
? Transmethylation Certain compounds of
the body, with structures containing
CH3 group attached to an atom other
than carbon can take part in enzymatic
reactions
? Whereby these ?CH3 groups are
transferred to a suitable "acceptor",
Text Book of Medical Biochemistry by Chatterjee & Rana Shinde, 8th Ed
which have no ?CH3 group
Cont--
? Such reactions are termed as "transmethylation reaction", and
the substrate, i.e. the ?CH3 donor is said to possess biologically
labile ?CH3 group"
? Most important compounds with biologically labile methyl group
are active methionine
Transmethylation reactions
Text Book of Medical Biochemistry by Chatterjee & Rana Shinde, 8th Ed
Group Discussion
? Subtopics of previous class discussed in groups.
Reference Books
1) Text Book of Medical Biochemistry by Chatterjee & Rana
Shinde, 8th Ed
2) Biochemistry, Lippincott's Il ustrated Reviews, 6th Ed
3) Harper's Il ustrated Biochemistry-30th Ed
4) Lehninger Principles of Biochemistry
33
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This post was last modified on 05 April 2022