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Multi Enzyme Complex: Sudhanshu Shekhar M.Tech (Biotech) III Sem A7110709009

A multienzyme complex is a protein possessing more than one catalytic domain contributed by distinct parts of a polypeptide chain ('domains'), or by distinct subunits, or both. i.e. a single enzyme is made up of one polypeptide chain, but when these polypeptide chain acts as a distinct part, and all act as a different enzyme having distinct catalytic domain, it is called multienzyme complex.

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Sudhanshu Shekhar
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19K views

Multi Enzyme Complex: Sudhanshu Shekhar M.Tech (Biotech) III Sem A7110709009

A multienzyme complex is a protein possessing more than one catalytic domain contributed by distinct parts of a polypeptide chain ('domains'), or by distinct subunits, or both. i.e. a single enzyme is made up of one polypeptide chain, but when these polypeptide chain acts as a distinct part, and all act as a different enzyme having distinct catalytic domain, it is called multienzyme complex.

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Sudhanshu Shekhar
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© Attribution Non-Commercial (BY-NC)
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Multi Enzyme Complex

Sudhanshu Shekhar
M.Tech (Biotech) IIIrd Sem
A7110709009
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Introduction: A multienzyme complex is a
protein possessing more than one catalytic
domain contributed by distinct parts of a
polypeptide chain ('domains'), or by distinct
subunits, or both.

i.e. a single enzyme is made up of one


polypeptide chain, but when these polypeptide
chain acts as a distinct part, and all act as a
different enzyme having distinct catalytic
domain, it is called multienzyme complex.
Examples
• Eukaryotes:
1. Pyruvate Dehydrogenase Complex
2. Cytochrome p450 enzyme:
metabolic intermediates such
as lipids and steroidal hormones, as well
as xenobiotic substances such as drugs and
other toxic chemicals. CYPs are the major enzymes
involved in drug metabolism and bioactivation,
accounting for ∼75% of the total metabolism.
3. Fatty acid synthase: Fatty acid synthase (FAS)
is a multi-enzyme that plays a key role in fatty acid
synthesis.
• Prokaryotes:
The Tryptophan Synthase: Tryptophan synthase is commonly
found in Eubacteria, Archaebacteria, Protista, Fungi, and Plantae.
Ex-Salmonella typhimurium

Tryptophan synthase was the first enzyme identified that had


two catalytic capabilities.

• The bifunctional tryptophan synthase α2β2 complex that catalyzes


the final two reactions in tryptophan biosynthesis is a classic
example of a multienzyme complex that "channels" a metabolic
intermediate (indole) between two active sites.
Pyruvate Dehydrogenase Complex
Glycolysis occurs in the cytosol of cells. Here,
one molecule of glucose (6c) is oxidized into
2x3c pyruvate. So, Pyruvate enters the
mitochondrion to be metabolized further.
Mitochondrial Compartment: The matrix
contains Pyruvate Dehydrogenase, enzymes
of Krebs Cycle, and other pathways, e.g.,
fatty acid oxidation & amino acid
metabolism.

Location: Mitochondrial matrix of


eukaryotic cells and in the Cytosol of
prokaryotes.

Pyruvate formed in the cytosol is transported


into the mitochondria by a proton symporter.
Pyruvate Dehydrogenase: a large complex
containing many copies of each of 3 enzymes,
E1, E2, & E3.
 The inner core of mammalian
Pyruvate Dehydrogenase is an
icosahedral structure consisting of
60 copies of E2.
 At the periphery of the complex
are:
• 30 copies of E1 (a tetramer with
subunits a2b2). A regular  polyhedron with
• 12 copies of E3 (a homodimer), 20 identical equilateral
plus 12 copies of an E3 triangular faces, 30 edges
binding protein that links E3 toand 12 vertices.
E 2.
The icosahedral structure of
pyruvate dehydrogenase complex
Pyruvate dehydrogenase multienzyme complex is the
gateway to the TCA cycle, producing acetyl CoA, by a
process called oxidative decarboxylation. It is a key
regulatory enzyme that directly modulates the rate of
glucose oxidation.

It is an irreversible oxidation process in which carboxyl


group is removed from pyruvate as a molecule of CO2 and
the two remaining carbons becomes the acetyl group of
acetyl CoA.

Pyruvate dehydrogenase complex


(E1+E2+E3)
Metabolic sources and fates of Acetyl Co A
Pyruvate dehydrogenase complex is a
noncovalent assembly of three enzymes and
five coenzymes.
E1 pyruvate dehydrogenase (24)
Es E2 dihydrolipoyl transacetylase (24)
E3 dihydrolipoyl dehydrogenase (12)

Thiamine pyrophosphate, TPP


HSCoA (pantothenic acid)
Cofactors Lipoic Acid
NAD+
FAD
Table 1: Cofactors for each component of
the PDH complex with the cofactor category
and vitamin source
Sub- Cofactor Type Vitamin Source
unit
E1 Thiamine Prosthetic Thiamine
pyrophosphate
E2 Coenzyme A Co-substrate Pantothenic acid
(Co-enzyme)
Lipoamide None - dietary
(lipoic acid + lys Prosthetic
residue)
E3 FAD Prosthetic Riboflavin

NAD+ Co-substrate Niacin


Pyruvate dehydrogenase complex:

HSCoA

NAD+
1. Pyruvate dehydrogenase
2. Dihydrolipoyl transacetylase
3. Dihydrolipoyl dehydrogenase

Hydroxyethyl TPP
Pyruvate

1
CO2

2
Acetyl
lipoamide
NADH
+H+
3

NAD+
2 CoASH
Dihydrolipoamide

Acetyl Co A
Figure: The reaction mechanism of Pyruvate Dehydrogenase Complex
Regulation:
Pyruvate dehydrogenase complex
• This Irreversible reaction is tightly controlled by
three ways:
• Allosteric Inhibition
 Inhibited by products: acetyl-CoA and NADH
 Inhibited by high ATP
• Allosteric activation by AMP
 Ratio ATP/AMP important
• Covalent modification (hormonal regulation)
 Through Phosphorylation/dephosphorylation of E1 subunit
 PDH exists in two forms:
Phosphorylated (inactive): Protein kinase enzyme converts
active into inactive enzyme active into inactive enzyme.
Dephosphorylated (active):Phosphatase enzyme converts
inactive into active.
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