? Sources of Amino Acids
? Amino Acid Utilization
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? Nitrogen Balance
? Amino-group metabolism
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? Transamination? Deamination
? Transdeamination
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? Transamidation
? Decarboxylation
? Transmethylation
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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
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small intestine, kidneys, seminal vesicles, and brain.
? He proposed a "cyclic" pathway/-glutamyl cycle in which
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Glutathione is regenerated again? -glutamyl transferases (GGT) plays a key role in this cycle, a
pathway for synthesis and degradation of glutathione and drug
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and xenobiotic detoxification
-glutamyl/Meister cycle
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Fig.26.1: Text Book of Medical Biochemistry by Chatterjee & Rana Shinde, 8th EdDisorder related to aa transporter
Hartnup disease: Defect in SCL6A19 gene, it is a sodium-
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dependent and chloride independent neutral aa transporter,expressed in kidneys and intestine
? This gene controls the absorption of certain aa from intestine
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and reabsorption of those aa in kidneys
? Person with Hartnup disease cannot absorb aa properly from
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intestine and cannot reabsorb them from tubules in kidneysCont--
? Resulting excessive amount of aa such as Trp excreted in urine
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? Due to inadequate amount of Trp, body not able to make sufficient
amount of niacin (vit B3), which is necessary component of NAD+
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? Pellagra, a similar condition, is also caused by low nicotinamide; thisdisorder results in dermatitis, diarrhea, and dementia
Cont--
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? Cystinuria: Dibasic (diamino aa) transporter Lys, Arg, Ornithineand Cys. If there is any defect in this transport system, it leads
to Cystinuria
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? In medicine, Garrod's tetrad is a term named for British
physician Archibald Garrod, who introduced the phrase "inborn
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errors of metabolism" in a lecture in 1908? Tetrad comprises four inherited metabolic diseases: albinism,
alkaptonuria, Cystinuria and pentosuria
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Fates of Amino Acids
? For Protein synthesis
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? For synthesis of other nitrogen containing compounds (heme,creatine, purines, pyrimidines, choline, neurotransmitters)
? For the gluconeogenesis
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? Energy source from glucogenic aa and ketogenic aa
Glucogenic aa: Give rise to a net production of pyruvate or TCA
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cycle intermediates, such as -ketoglutarate , succinyl CoA,Fumarate and oxaloacetate, all of which are precursors to
glucose via gluconeogenesis. Ex. Ala & Arg
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Cont--Ketogenic aa: Lysine and leucine are the only aa are ketogenic,
giving rise only to acetylCoA or acetoacetylCoA, neither of which
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can bring about net glucose production. Ex. Leu and Lys
Glucogenic and Ketogenic aa: Small group of aa comprised of
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Ile, Phe, Thr, Trp, and Tyr give rise to both glucose and fatty acidprecursors and characterized as glucogenic and ketogenic
Sources of Amino Acids
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? Ingested dietary proteins is hydrolysed to aa and absorbed from
the intestine
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? Breakdown of tissue/body proteins? Glycolysis and citric acid cycle
? Synthesis of non-essential aa
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Amino Acid UtilizationDegradation of an aa in two
stages:
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a) Carbon skeleton, is then converted to
pyruvate, acetyl CoA, or citric acid cycle
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intermediate, depending on its makeup,with the resulting energy production or
energy storage
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b) Amino nitrogen atom is removed and
converted to ammonium ion, which
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ultimately is excreted from the body asurea.
Nitrogen Balance
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Nitrogen balance occurs when synthesis of body protein equals
degradation.
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? Amount of nitrogen excreted in the urine each day equals theamount of nitrogen ingested each day
Positive nitrogen balance occurs when synthesis of body protein
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excess compare to degradation.
? Less nitrogen is excreted than ingested (growth, e.g. growing
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infants and children, pregnant women, tissue repair)Cont--
Negative nitrogen balance occurs when synthesis of body protein
lesser compare to degradation.
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? More nitrogen is excreted than ingested (malnutrition, absence
of one or more essential aa in diet)
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? It occurs in injury, stress response, malnutrition of essential aaAmino-group metabolism
? -amino group is the nitrogen source during aa
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metabolism
? Nitrogen is removed from aa as a ammonia,
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which needs to be detoxified to ureaThree steps involved in flow of nitrogen from aa to
urea:
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(1) Transamination (amino group transferred toglutamate),
(2) Oxidative deamination of glutamate (removal of
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amino group),
(3) Synthesis of Urea
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Fig 19.15. Lippincott's Illustrated Reviews, Biochemistry, 6th EdTransamination
? -NH2 group of one aa is transferred
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to a -ketoacid resulting in formationof a new aa and a new ketoacid
? Donor aa (I) becomes a new
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ketoacid (I) after losing the -NH2
group, and recipient ketoacid (II)
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becomes a new aa (II) afterreceiving the NH2 group
Text Book of Medical Biochemistry by Chatterjee & Rana Shinde, 8th Ed
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Cont--
? -amino group from L-amino acid is
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transferred to -carbon atom of -ketoglutarate, produced -keto acid and
glutamate
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? Transfer of amino groups from one carbon
skeleton to another is catalyzed by
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aminotransferases? Al aminotransferases have prosthetic group,
which is pyridoxal phosphate (PLP),
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coenzyme form of pyridoxine or vitamin B
Fig18.4: Lehninger Principles of Biochemistry by David L Nelson
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6Cont--
? Transfer of an -amino group from one aa to an
-keto acid in a reversible reaction
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? Location: cytoplasm of all cells
? Enzyme: Transaminases (aminotransferases)
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? Co-factor: Pyridoxal phosphate (PLP), derivativeof vitamin B6
? Common donor/acceptor pair: -ketoglutarate and
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glutamate
Cont--
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? Glutamate then functions as excretion pathways that lead to theelimination of nitrogenous waste products
? Al aa except lysine and threonine participate in transamination
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in their catabolism but they undergo deamination reaction
? Two aminotransferase reactions are catalyzed by alanine
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aminotransferase (ALT ) and aspartate transferases (AST)Cont--
Alanine aminotransferase
? In this alanine is the donor aa and -
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ketoglutarate is the recipient ketoacid resultingin formation of pyruvate and glutamate.
? During amino acid catabolism, this enzyme
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functions in the direction of glutamate synthesis.
Aspartate aminotransferase
? In this Aspartic acid is the donor amino acid and
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-ketoglutarate is the recipient ketoacid.
? During aa catabolism, this enzyme transfers
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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
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nitrogen in the urea cycle.
Diagnostic value of plasma aminotransferases
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Alanine aminotransferase? Normal enzyme activity is 3 to 15 IU/L
? It is entirely cytoplasmic
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? Increases in viral hepatitis, diabetes, congestive heart failure, liverdamage
Aspartate aminotransferase
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? Normal enzyme activity is 4 to 17 I.U/L? It is cytoplasmic and also mitochondrial
? Increases in Liver diseases, muscular dystrophies, acute
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pancreatitis, leukaemias, acute haemolytic anaemia
Deamination
? In oxidative deamination reactions result in the
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liberation of the amino group as free ammonia
? Amino groups from many of the -aa are collected
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in the liver in the form of the amino group of L-glutamate molecules
? These amino groups must next be removed from
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L-Glutamate semialdehyde
glutamate to prepare them for excretion
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? In hepatocytes, glutamate is transported from thecytosol into mitochondria, where it undergoes
oxidative deamination catalyzed by L-glutamate
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Fig18.7: Lehninger Principles of Biochemistry by David L Nelson
dehydrogenase
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Cont--? It is the only enzyme that can use either NAD+ or NADP+ as the
acceptor of reducing equivalents
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? This oxidative deamination of glutamate is the main mechanism for
release of aa nitrogen as ammonia (NH +) in a reversible reaction.
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4? Location: Mitochondria of hepatocytes
? Allosteric regulation of oxidative deamination: High energy state
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inhibits the GDH and low energy state stimulates the enzyme.
Transdeamination
? Transfer of amino nitrogen to -ketoglutarate forms l-
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glutamate.
? Hepatic l-glutamate dehydrogenase (GDH), which can use
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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
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"transdeamination"
Cont--
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? Liver GDH activity is allosterically inhibited by ATP, GTP, andNADH, and is activated by ADP
? GDH reaction is freely reversible, and also functions in aa
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biosynthesis
? The -ketoglutarate formed from glutamate deamination can be
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used in the citric acid cycle and for glucose synthesisTransamidation
? Transamidation involves transfer of ?NH2 from a
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carboxamide group to a suitable acceptor? Formation of glucosamine-6-P:The amide-N of glutamine
can be transferred to a ketogroup
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? If transferred to a Keto group of fructose-6-P, it forms
Glucosamine-6-P by a transamidation reaction from
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Glutamine as the 1st step of hexosamine biosynthesispathway
Text Book of Medical Biochemistry by Chatterjee & Rana Shinde, 8th Ed
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Decarboxylation
? Reaction by which CO2 is removed
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from the COOH group of an aa as aresult an amine is formed
? This reaction is catalysed by
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decarboxylase,
which
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requirespyridoxal-P (B6-PO4) as coenzyme
Text Book of Medical Biochemistry by Chatterjee & Rana Shinde, 8th Ed
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? The enzyme removes CO2 from COOH
gr.
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andconverts
the
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aa
to
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corresponding amineCont--
? End-product of this pathway is UDP-GlcNAc, used to make
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glycosaminoglycans, proteoglycans and glycolipids? The catalysing enzyme is L-glutamine-D-fructose-6-P
transamidase
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Cont--
? This is mostly a process confined to putrefaction in intestines
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and produces amines? Ex. Threonine is converted into Propanol amine (Constituent of
Vit B12)
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? Isoleucine undergoes transamination, followed by oxidative
decarboxylation of resulting -keto acid
Transmethylation
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? Transmethylation Certain compounds of
the body, with structures containing
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CH3 group attached to an atom otherthan carbon can take part in enzymatic
reactions
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? Whereby these ?CH3 groups are
transferred to a suitable "acceptor",
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Text Book of Medical Biochemistry by Chatterjee & Rana Shinde, 8th Edwhich have no ?CH3 group
Cont--
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? Such reactions are termed as "transmethylation reaction", and
the substrate, i.e. the ?CH3 donor is said to possess biologically
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labile ?CH3 group"? Most important compounds with biologically labile methyl group
are active methionine
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Transmethylation reactionsText Book of Medical Biochemistry by Chatterjee & Rana Shinde, 8th Ed
Group Discussion
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? Subtopics of previous class discussed in groups.
Reference Books
1) Text Book of Medical Biochemistry by Chatterjee & Rana
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Shinde, 8th Ed
2) Biochemistry, Lippincott's Il ustrated Reviews, 6th Ed
3) Harper's Il ustrated Biochemistry-30th Ed
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4) Lehninger Principles of Biochemistry33
Thank you
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