Download MBBS Biochemistry PPT 33 Amino Acid Oxidation Lecture Notes

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Specific Learning Objectives

Fates of Amino Acids
Amino Acid Utilization
Amino-group metabolism

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Explain role of transamination reactions in aa synthesis and identify vitamin

essential for this reaction (tie in to urea cycle)

Describe interconversion between ketoacids and aa, including requirement of

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pyridoxal phosphate (PLP) as a cofactor

Outline formation and transport of ammonia
Describe importance of reactions catalyzed by glutamine synthetase, glutaminase,

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and glutamate dehydrogenase

Ammonia Intoxication
List causes for hyperammonemia, its consequences, and treatments to reduce

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blood ammonia levels
Overview of AA catabolism

Fig18.1: Lehninger Principles of Biochemistry by David L Nelson, 6th Ed

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Amino Acid oxidative degradation

It occurs in three metabolic circumstances:
1. During normal synthesis and degradation of Proteins (Protein turnover)

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? Some aa released from proteins breakdown and not needed for new protein

synthesis

2. If diet is rich in protein and ingested aa exceeds the body needs for protein

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synthesis, in this case surplus catabolized

2. During starvation or in uncontrolled diabetes, when carbohydrates either

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unavailable or not properly utilized, in this case cellular proteins are used as a

fuel
Cont--

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Under all above conditions, aa lose their amino groups to form -keto acids and

also form carbon skeletons of aa:

? -keto acids undergo oxidation to CO and H O

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2

2

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? 3-4 carbon units its converted into glucose by gluconeogenesis, fuel for brain,

skeletal muscel and other tissues

Four aa plays imp role in nitrogen metabolism: Glutamate, Glutamine, (both

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converted to -ketoglutarate), Alanine (to pyruvate) and Aspartate (to

oxaloacetate)

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Fates of Amino Acids

For Protein synthesis
For synthesis of other nitrogen containing compounds (heme, creatine,

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purines, pyrimidines, choline, neurotransmitters)

For gluconeogenesis
Energy source from glucogenic aa and ketogenic aa

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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.

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Ex. Ala & Arg
Cont--

Ketogenic aa: Lysine and leucine are only aa are ketogenic, give rise to

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acetyl-CoA or acetoacetyl-CoA, neither of which can bring about net

glucose production

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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

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Steps for Amino group catabolism

In cytosol of liver cells, amino groups from most aa transferred to -

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ketoglutarate to form glutamate, which enters mitochondria and gives up its

amino group to form ammonia

Excess ammonia generated in most tissues converted to amide nitrogen of

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glutamine, which passes to liver, then into liver mitochondria

In skeletal muscle, excess amino groups are transferred to pyruvate to form

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alanine

Aspartate come into play in metabolic processes that occur once amino

groups delivered to liver

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Amino group catabolism

Fig18.2 (a): Lehninger Principles of Biochemistry by David L Nelson, 6th Ed

Amino Acid Utilization

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Degradation of an aa in two stages:

a) Carbon skeleton, is then converted to

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pyruvate, acetyl CoA, or citric acid cycle

intermediate, depending on its makeup,

with resulting energy production or

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energy storage

b) Amino nitrogen atom is removed and

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converted to ammonium ion, which

ultimately excreted from body as urea.
Amino-group metabolism

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? -amino group is nitrogen source during aa

metabolism

? Nitrogen is removed from aa as a ammonia, which

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needs to be detoxified to urea

Three steps involved in flow of nitrogen from aa to

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urea:
(1) Transamination (amino group transferred to

glutamate),

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(2) Oxidative deamination of glutamate (removal of

amino group),

(3) Synthesis of Urea

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Fig 19.15. Lippincott's Illustrated Reviews, Biochemistry, 6th Ed

Transamination

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? -NH2 group of one aa is transferred

to a -ketoacid resulting in formation

of a new aa and a new ketoacid

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? Donor aa (I) becomes a new ketoacid

(I) after losing the -NH2 group, and

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recipient ketoacid (II) becomes a new

aa (II) after receiving 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

transferred to -carbon atom of -

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ketoglutarate, produced -keto acid and

glutamate

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? Transfer of amino groups from one carbon

skeleton to another is catalyzed by

aminotransferases

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? 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

6

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Cont--

? PLP participates in transfer of -amino groups to -

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ketoglutarate

? Location: cytoplasm of all cells

? Enzyme: Transaminases (aminotransferases)

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? Co-factor: Pyridoxal phosphate (PLP), derivative of

vitamin B6

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? Common donor/acceptor pair: -ketoglutarate and

glutamate
Cont--

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Glutamate function as excretion pathways that lead to elimination of

nitrogenous waste products

Al aa except lysine and threonine participate in transamination in

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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 donor aa and

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-ketoglutarate is recipient ketoacid resulting in formation

of pyruvate and glutamate.
? During aa catabolism, this enzyme functions in direction

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of glutamate synthesis.

Aspartate aminotransferase: In this Aspartic acid is donor

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aa and -ketoglutarate is recipient ketoacid.
? During aa catabolism, this enzyme transfers amino

groups from glutamate to oxaloacetate, forming

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aspartate, which is used as a source of nitrogen in urea

cycle.

Fig 19.8. Lippincott's Illustrated Reviews, Biochemistry, 6th Ed

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Diagnostic value of plasma aminotransferases

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, liver

damage

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 pancreatitis,

leukaemias, acute haemolytic anaemia

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Oxidative Deamination

? Glutamate releases its amino group as ammonia in

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Liver

? Amino groups from many of -aa are collected in liver

in form of amino group of L-glutamate molecules

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L-Glutamate semialdehyde

? These amino groups must next be removed from

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glutamate to prepare them for excretion

? In hepatocytes, glutamate is transported from cytosol

into mitochondria, where it undergoes oxidative

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deamination

catalyzed

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by

L-glutamate

Fig18.7: Lehninger Principles of Biochemistry by David L Nelson, 6th Ed

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dehydrogenase
Cont--

It is only enzyme that can use either NAD+ or NADP+ as acceptor of

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reducing equivalents

Oxidative deamination of glutamate is main mechanism for release of

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aa nitrogen as ammonia (NH4+) in a reversible reaction.

Location: Mitochondria of hepatocytes

Al osteric regulation of oxidative deamination: High energy state inhibits

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GDH and low energy state stimulates enzyme.

Transdeamination

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Transfer of amino nitrogen to -ketoglutarate forms l-glutamate by

glutamate aminotransferases

Hepatic l-glutamate dehydrogenase (GDH), which can use either NAD+ or

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NADP+, convert glutamate to -ketoglutarate, releases this nitrogen as

ammonia, this -ketoglutarate used in TCA cycle and glucose synthesis

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Conversion of -amino nitrogen to ammonia by coordinated action of

glutamate aminotransferase and GDH is "transdeamination"
Cont--

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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

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biosynthesis

-ketoglutarate formed from glutamate deamination can be used in

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citric acid cycle and for glucose synthesis

Clinical-cases discussed
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