This document provides an overview of protein structure and function. It discusses the hierarchical structure of proteins from primary to quaternary structure. Key points include:
- Proteins fold into complex 3D structures determined by their amino acid sequence.
- Protein function depends on their structure, which can be regulated by modifications or degradation.
- Enzymes catalyze reactions by lowering activation energy through complementary transition state binding.
- Chaperones assist protein folding to prevent misfolding and aggregation.
- Mutations can lead to misfolded proteins associated with neurodegenerative diseases.
Structural bioinformatics deals with prediction of 3-D structures of biological macromolecules such as proteins, DNA, RNA etc., basing on the data obtained from studies with the help of technique like X-ray crystallography, NMR etc. PDB is now essential for any study in structural biology. It is a freely accessible database of biological macromolecules.
Introduction:
Protein
Protein motif.
2. History:
3. A brief overview of protein structure.
4. The Structural Classification of Protein(SCOP):
All α.
All β
α/β
α+β
5.The super secondary structure.
6. Rules for formation of Protein Motifs.
7. Structural motifs.
8. Some Common Protein Motifs:
β-hairpin.
β-meander.
Alpha-alpha corner.
Helix-turn-helix motif.
β-α-β motif.
β-sandwich.
β-barrel.
Greek key.
The Jellyroll topology.
Omega loop.
Zinc finger motif.
9. Conclusion.
10. References.
Structural bioinformatics deals with prediction of 3-D structures of biological macromolecules such as proteins, DNA, RNA etc., basing on the data obtained from studies with the help of technique like X-ray crystallography, NMR etc. PDB is now essential for any study in structural biology. It is a freely accessible database of biological macromolecules.
Introduction:
Protein
Protein motif.
2. History:
3. A brief overview of protein structure.
4. The Structural Classification of Protein(SCOP):
All α.
All β
α/β
α+β
5.The super secondary structure.
6. Rules for formation of Protein Motifs.
7. Structural motifs.
8. Some Common Protein Motifs:
β-hairpin.
β-meander.
Alpha-alpha corner.
Helix-turn-helix motif.
β-α-β motif.
β-sandwich.
β-barrel.
Greek key.
The Jellyroll topology.
Omega loop.
Zinc finger motif.
9. Conclusion.
10. References.
Primary structure of protein
Secondary structure of protein
Tertiary structure of protein
Quaternary structure of protein
Methods to determine protein structure
Conclusion
References
METHODS TO DETERMINE PROTEIN STRUCTURE
Each protein has a unique sequence of amino acids.
The amino acids are held together in a protein by
covalent peptide bonds or linkages.
A peptide bond are formed when amino group of an
amino acid combines with the carboxyl group of another.
The conformation of polypeptide chain by twisting or folding is referred to as secondary structure.
Two types of secondary structures α-helix and β-sheet are mainly identified.
α-Helical structure was proposed by Pauling and Corey in 1951.
It occurs when the sequence of amino acids are linked by hydrogen bonds.
Each turn of α-helix contains 3.6 amino acids.
β-pleated sheets are composed of two or more segments of fully extended peptide chains.
β-Sheets may be arranged either in parallel or anti-parallel direction.
Many globular proteins contain combinations of α-helix and β-pleated sheet secondary structure, these patterns are called supersecondary structures also called motifs.
The three dimensional arrangement of protein structure is referred to as tertiary structure.
It is a compact structure with hydrophobic side chains held interior while the hydrophilic groups are on the surface.
This type of arrangement provide stability of the molecule.
Besides the H-bongs, disulfide bonds, ionic interactions, hydrophobic interactions also contribute to the tertiary structure.
Proteins are polypeptide structures made up of one or more extended chains of residues from the amino acid. They provide a wide range of organism tasks, including as DNA replication, molecule transport, metabolic process catalysis, and cell structural support.
The albumins seen in vast quantities in egg whites typically have a distinct 3D structure as a result of bonds that form between the protein’s various amino acids. These bonds are broken by heating, exposing the hydrophobic (water-hating) amino acids that are typically maintained on the inside of the protein 1, 1 comma, 2 end superscript, 2, start superscript. In an effort to escape the water that surrounds them in the egg white, the hydrophobic amino acids will bind to one another, creating a protein network that gives the egg white structure and makes it white and opaque. Ta-da! Protein denaturation, thank you for another wonderful breakfast
INTRODUCTION OF MACROMOLECULE
HISTORY OF MACROMOLECULE
PROPERTIES
TYPES OF MACROMOLECULE
COMPLEX FORMATION
EXAMPLE-
Chromatin
Ribosome
CONCLUSION
REFERENCES
Primary structure of protein
Secondary structure of protein
Tertiary structure of protein
Quaternary structure of protein
Methods to determine protein structure
Conclusion
References
METHODS TO DETERMINE PROTEIN STRUCTURE
Each protein has a unique sequence of amino acids.
The amino acids are held together in a protein by
covalent peptide bonds or linkages.
A peptide bond are formed when amino group of an
amino acid combines with the carboxyl group of another.
The conformation of polypeptide chain by twisting or folding is referred to as secondary structure.
Two types of secondary structures α-helix and β-sheet are mainly identified.
α-Helical structure was proposed by Pauling and Corey in 1951.
It occurs when the sequence of amino acids are linked by hydrogen bonds.
Each turn of α-helix contains 3.6 amino acids.
β-pleated sheets are composed of two or more segments of fully extended peptide chains.
β-Sheets may be arranged either in parallel or anti-parallel direction.
Many globular proteins contain combinations of α-helix and β-pleated sheet secondary structure, these patterns are called supersecondary structures also called motifs.
The three dimensional arrangement of protein structure is referred to as tertiary structure.
It is a compact structure with hydrophobic side chains held interior while the hydrophilic groups are on the surface.
This type of arrangement provide stability of the molecule.
Besides the H-bongs, disulfide bonds, ionic interactions, hydrophobic interactions also contribute to the tertiary structure.
Proteins are polypeptide structures made up of one or more extended chains of residues from the amino acid. They provide a wide range of organism tasks, including as DNA replication, molecule transport, metabolic process catalysis, and cell structural support.
The albumins seen in vast quantities in egg whites typically have a distinct 3D structure as a result of bonds that form between the protein’s various amino acids. These bonds are broken by heating, exposing the hydrophobic (water-hating) amino acids that are typically maintained on the inside of the protein 1, 1 comma, 2 end superscript, 2, start superscript. In an effort to escape the water that surrounds them in the egg white, the hydrophobic amino acids will bind to one another, creating a protein network that gives the egg white structure and makes it white and opaque. Ta-da! Protein denaturation, thank you for another wonderful breakfast
INTRODUCTION OF MACROMOLECULE
HISTORY OF MACROMOLECULE
PROPERTIES
TYPES OF MACROMOLECULE
COMPLEX FORMATION
EXAMPLE-
Chromatin
Ribosome
CONCLUSION
REFERENCES
Similar to Protein structure and receptor function (19)
These simplified slides by Dr. Sidra Arshad present an overview of the non-respiratory functions of the respiratory tract.
Learning objectives:
1. Enlist the non-respiratory functions of the respiratory tract
2. Briefly explain how these functions are carried out
3. Discuss the significance of dead space
4. Differentiate between minute ventilation and alveolar ventilation
5. Describe the cough and sneeze reflexes
Study Resources:
1. Chapter 39, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 34, Ganong’s Review of Medical Physiology, 26th edition
3. Chapter 17, Human Physiology by Lauralee Sherwood, 9th edition
4. Non-respiratory functions of the lungs https://academic.oup.com/bjaed/article/13/3/98/278874
Lung Cancer: Artificial Intelligence, Synergetics, Complex System Analysis, S...Oleg Kshivets
RESULTS: Overall life span (LS) was 2252.1±1742.5 days and cumulative 5-year survival (5YS) reached 73.2%, 10 years – 64.8%, 20 years – 42.5%. 513 LCP lived more than 5 years (LS=3124.6±1525.6 days), 148 LCP – more than 10 years (LS=5054.4±1504.1 days).199 LCP died because of LC (LS=562.7±374.5 days). 5YS of LCP after bi/lobectomies was significantly superior in comparison with LCP after pneumonectomies (78.1% vs.63.7%, P=0.00001 by log-rank test). AT significantly improved 5YS (66.3% vs. 34.8%) (P=0.00000 by log-rank test) only for LCP with N1-2. Cox modeling displayed that 5YS of LCP significantly depended on: phase transition (PT) early-invasive LC in terms of synergetics, PT N0—N12, cell ratio factors (ratio between cancer cells- CC and blood cells subpopulations), G1-3, histology, glucose, AT, blood cell circuit, prothrombin index, heparin tolerance, recalcification time (P=0.000-0.038). Neural networks, genetic algorithm selection and bootstrap simulation revealed relationships between 5YS and PT early-invasive LC (rank=1), PT N0—N12 (rank=2), thrombocytes/CC (3), erythrocytes/CC (4), eosinophils/CC (5), healthy cells/CC (6), lymphocytes/CC (7), segmented neutrophils/CC (8), stick neutrophils/CC (9), monocytes/CC (10); leucocytes/CC (11). Correct prediction of 5YS was 100% by neural networks computing (area under ROC curve=1.0; error=0.0).
CONCLUSIONS: 5YS of LCP after radical procedures significantly depended on: 1) PT early-invasive cancer; 2) PT N0--N12; 3) cell ratio factors; 4) blood cell circuit; 5) biochemical factors; 6) hemostasis system; 7) AT; 8) LC characteristics; 9) LC cell dynamics; 10) surgery type: lobectomy/pneumonectomy; 11) anthropometric data. Optimal diagnosis and treatment strategies for LC are: 1) screening and early detection of LC; 2) availability of experienced thoracic surgeons because of complexity of radical procedures; 3) aggressive en block surgery and adequate lymph node dissection for completeness; 4) precise prediction; 5) adjuvant chemoimmunoradiotherapy for LCP with unfavorable prognosis.
Ethanol (CH3CH2OH), or beverage alcohol, is a two-carbon alcohol
that is rapidly distributed in the body and brain. Ethanol alters many
neurochemical systems and has rewarding and addictive properties. It
is the oldest recreational drug and likely contributes to more morbidity,
mortality, and public health costs than all illicit drugs combined. The
5th edition of the Diagnostic and Statistical Manual of Mental Disorders
(DSM-5) integrates alcohol abuse and alcohol dependence into a single
disorder called alcohol use disorder (AUD), with mild, moderate,
and severe subclassifications (American Psychiatric Association, 2013).
In the DSM-5, all types of substance abuse and dependence have been
combined into a single substance use disorder (SUD) on a continuum
from mild to severe. A diagnosis of AUD requires that at least two of
the 11 DSM-5 behaviors be present within a 12-month period (mild
AUD: 2–3 criteria; moderate AUD: 4–5 criteria; severe AUD: 6–11 criteria).
The four main behavioral effects of AUD are impaired control over
drinking, negative social consequences, risky use, and altered physiological
effects (tolerance, withdrawal). This chapter presents an overview
of the prevalence and harmful consequences of AUD in the U.S.,
the systemic nature of the disease, neurocircuitry and stages of AUD,
comorbidities, fetal alcohol spectrum disorders, genetic risk factors, and
pharmacotherapies for AUD.
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Tom Selleck Health: A Comprehensive Look at the Iconic Actor’s Wellness Journeygreendigital
Tom Selleck, an enduring figure in Hollywood. has captivated audiences for decades with his rugged charm, iconic moustache. and memorable roles in television and film. From his breakout role as Thomas Magnum in Magnum P.I. to his current portrayal of Frank Reagan in Blue Bloods. Selleck's career has spanned over 50 years. But beyond his professional achievements. fans have often been curious about Tom Selleck Health. especially as he has aged in the public eye.
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Introduction
Many have been interested in Tom Selleck health. not only because of his enduring presence on screen but also because of the challenges. and lifestyle choices he has faced and made over the years. This article delves into the various aspects of Tom Selleck health. exploring his fitness regimen, diet, mental health. and the challenges he has encountered as he ages. We'll look at how he maintains his well-being. the health issues he has faced, and his approach to ageing .
Early Life and Career
Childhood and Athletic Beginnings
Tom Selleck was born on January 29, 1945, in Detroit, Michigan, and grew up in Sherman Oaks, California. From an early age, he was involved in sports, particularly basketball. which played a significant role in his physical development. His athletic pursuits continued into college. where he attended the University of Southern California (USC) on a basketball scholarship. This early involvement in sports laid a strong foundation for his physical health and disciplined lifestyle.
Transition to Acting
Selleck's transition from an athlete to an actor came with its physical demands. His first significant role in "Magnum P.I." required him to perform various stunts and maintain a fit appearance. This role, which he played from 1980 to 1988. necessitated a rigorous fitness routine to meet the show's demands. setting the stage for his long-term commitment to health and wellness.
Fitness Regimen
Workout Routine
Tom Selleck health and fitness regimen has evolved. adapting to his changing roles and age. During his "Magnum, P.I." days. Selleck's workouts were intense and focused on building and maintaining muscle mass. His routine included weightlifting, cardiovascular exercises. and specific training for the stunts he performed on the show.
Selleck adjusted his fitness routine as he aged to suit his body's needs. Today, his workouts focus on maintaining flexibility, strength, and cardiovascular health. He incorporates low-impact exercises such as swimming, walking, and light weightlifting. This balanced approach helps him stay fit without putting undue strain on his joints and muscles.
Importance of Flexibility and Mobility
In recent years, Selleck has emphasized the importance of flexibility and mobility in his fitness regimen. Understanding the natural decline in muscle mass and joint flexibility with age. he includes stretching and yoga in his routine. These practices help prevent injuries, improve posture, and maintain mobilit
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Protein structure and receptor function
1. Chap.3 Protein Structure & Function
Topics
• Hierarchical Structure of
Proteins
• Protein Folding
• Examples of Protein Function-
Ligand-binding Proteins &
Enzymes
• Regulating Protein Function by
Protein Degradation
• Regulating Protein Function by
Noncovalent and Covalent
Modifications
Goals
Learn the basic structure and
properties of proteins and
enzymes, which carry out most
of the work in cells (Fig. 3.1).
2. Overview of Protein Structure Hierarchy
The four levels of
protein structure are
illustrated in Fig. 3.2.
A detailed discussion
of each of these levels
is presented in the
next few slides.
Experiments have
shown that the final
3D tertiary structure
of a protein ultimately
is determined by the
primary structure
(amino acid sequence).
The 3D fold (shape) of
the protein determines
its function.
3. Primary Structure
The primary structure of a
protein refers to its amino acid
sequence. Amino acids in peptides
(<30 aas) and proteins (typically
200 to 1,000 aas) are joined
together by peptide bonds (amide
bonds) between the carboxyl and
amino groups of adjacent amino
acids (Fig. 3.3). The backbone of
all proteins consists of a [-N-
Ca(R)-C(O)-] repetitive unit.
Only the R-group side-chains
vary. By convention, protein
sequences are written from left-
to-right, from the protein’s N-
to C-terminus. The average yeast
protein contains 466 amino acids.
Because the average molecular
weight of an amino acid is 113
daltons (Da), the average
molecular weight of a yeast
protein is 52,728 Da. Note that
1 Da = 1 a.m.u. (1 proton mass).
N
Ca(R)
4. Secondary Structure: a Helix
Secondary structure refers to
short-range, periodic folding
elements that are common in
proteins. These include the a helix,
the b sheet, and turns. In the a
helix (Fig. 3.4), the backbone
adopts a cylindrical spiral structure
in which there are 3.6 aas per
turn. The R-groups point out from
the helix, and mediate contacts to
other structure elements in the
folded protein. The a helix is
stabilized by H-bonds between
backbone carbonyl oxygen and amide
nitrogen atoms that are oriented
parallel to the helix axis. H-bonds
occur between residues located in
the n and n + 4 positions relative to
one another.
5. Secondary Structure: b Sheets & Turns
In b sheets (a.k.a. “pleated
sheets”), each b strand adopts an
extended conformation (Fig. 3.5).
ß strands tend to occur in pairs
or multiple copies in b sheets
that interact with one another
via H-bonds directed
perpendicular to the axis of each
strand. Carbonyl oxygens and
amide nitrogens in the strands
form the H-bonds. Strands can
orient antiparallel (Fig. 3.5a) or
parallel (not shown) to one
another in b sheets. R-groups of
every other amino acid point up
or down relative to the sheet
(Fig. 3.5b). Most ß strands in
proteins are 5 to 8 aas long. ß
Turns consist of 3-4 amino acids
that form tight bends (Fig. 3.6).
Glycine and proline are common in
turns. Longer connecting
segments between ß strands are
called loops.
ß turn
6. Tertiary Structure
Tertiary structure refers to the
folded 3D structure of a protein.
It is also known as the native
structure or active conformation.
Tertiary structure mostly is
stabilized by noncovalent
interactions between secondary
structure elements and other
internal sequence regions that
cannot be classified as a particular
type of secondary structure. The
folding of proteins is thought to
be driven by the need to place the
most hydrophobic regions in the
interior out of contact with water
(Fig. 3.7). The structures of
hundreds of proteins have been
determined by techniques such as
x-ray crystallography and NMR.
Different methods of representing
structures are shown in Fig. 3.8.
Keep in mind that most proteins are somewhat flexible and
undergo subtle conformational changes while carrying out their
functions.
7. Secondary Structure Motifs
Secondary structure motifs are evolutionarily conserved
collections of secondary structure elements which have a defined
conformation. They also have a consensus sequence because the
aa sequence ultimately determines structure. A given motif can
occur in a number of proteins where it carries out the same or
similar functions. Some well known examples such as the coiled-
coil, EF hand/helix-loop-helix, and zinc-finger motifs are
illustrated in Fig. 3.9. These motifs typically mediate protein-
protein association, calcium/DNA binding, and DNA or RNA
binding, respectively.
8. Quaternary Structure
Multisubunit (multimeric)
proteins have another level
of structural organization
known as quaternary
structure. Quaternary
structure refers to the
number of subunits, their
relative positions, and
contacts between the
individual monomers in a
multimeric protein. The
quaternary structure of
the trimeric hemagglutinin
surface protein of
influenza virus is shown in
Fig. 3.10b. The tertiary
structure of a
hemagglutinin monomer is
shown in Fig. 3.10a.
9. Modular Domain Structure of Proteins
Domains are independently folding and functionally specialized
tertiary structure units within a protein. The respective
globular and fibrous structural domains of the hemagglutinin
monomer (which happen to be individual polypeptide chains) are
illustrated above in Fig. 3.10a. Domains (such as the EGF
domain) also may be encoded within a single polypeptide chain,
as illustrated in Fig. 3.11. Domains still perform their
standard functions although fused together in a longer
polypeptide (e.g., DNA binding and ATPase domains of a
transcription factor). The modular domain structure of many
proteins has resulted from the shuffling and splicing together
of their coding sequences within longer genes.
Epidermal growth
factor (EGF) domain
10. Supramolecular Structure
In many cases, multimeric proteins
achieve extremely large sizes,
e.g., 10s-100s of subunits. Such
complexes exhibit the highest level
of structural organization known as
supramolecular structure. Examples
include mRNA transcription
preinitiation complexes (Fig. 3.12),
ribosomes, proteasomes, and
spliceosomes. Typically,
supramolecular complexes function
as ”macromolecular machines" in
reference to the fact that the
activities of individual subunits are
coordinated in the performance of
some overall task (e.g., protein
synthesis by the ribosome).
11. Evolution of Protein Families
Through genome sequencing
and classical gene cloning
approaches, the sequences
of an enormous number of
proteins have been compiled.
Comparison of sequences
shows that most proteins
belong to larger families
that have evolved over time
from a common ancestor
protein, as illustrated for
the globin family of O2
binding proteins (Fig. 3.13).
Proteins that have a common
ancestor are called
homologs. The members of a
protein family often show
>30% sequence ID, have a
common 3D fold, and usually
perform closely related
functions.
12. Structure of the Globin Proteins
These globular proteins are composed of mostly a helical
secondary structure. The similar folds of the globins can be
readily seen by comparing the structures of the b chain of
hemoglobin, myoglobin, and leghemoglobin (Fig. 3.13). The closely
similar structures of mammalian myoglobin and the hemoglobin b
subunit might be expected, but the resemblance of the distantly
related plant leghemoglobin is
striking. Comparison of the
sequences of the members of
protein families has brought
to light the fact that amino
acids within a given class
exhibit a large degree of
functional redundancy. In
this regard, the 3 proteins
discussed here exhibit less
than 20% identity in their
sequences, yet have the
same structure. Lastly, in
hemoglobin 2 different globin
chains have combined to form
a multisubunit protein.
13. Overview of Protein Folding
Many experiments have shown that
proteins can spontaneously fold
from an unfolded state to their
folded native state. This proves
that the amino acid sequence
contains enough information to
specify tertiary structure. Bonds
within the peptide backbone seek
out different possible
conformations as the final tertiary
structure is achieved (Fig. 3.14).
Folding tends to occur via
successive conformational changes
leading to secondary and then
tertiary structure elements (Fig.
3.15). The native conformation of
a protein typically is its lowest
free energy, and therefore, most
stable structure. The unfolded
(denatured) conformation of a
protein can be generated by
heating or treatment with certain
organic solvents.
14. Chaperone-assisted Protein Folding
The folding of many proteins, particularly large ones, is
kinetically slow and is assisted in vivo by folding agents known as
chaperones. These proteins are found in all organisms and even in
different organelles of eukaryotic cells. Chaperones assist in 1)
folding of nascent polypeptides made by translation, and 2) re-
folding of proteins denatured by environmental damage, such as
heat shock. Molecular chaperones bind to unfolded nascent
polypeptide chains as they
emerge from the ribosome,
and prevent aggregation,
misfolding, and degradation
(Fig. 3.16a). The hydrolysis
of ATP by the chaperone
drives conformational
changes that prevent
aggregation and help drive
protein folding. Accessory
proteins participate in the
process. Eukaryotic
molecular chaperones such
as Hsp 70 (cytosol & mito
matrix) and BiP (ER) are
related to the bacterial
protein DnaK.
15. Eukaryotic chaperonins such as the TriC complex are large
multimeric complexes related to the bacterial GroEL and GroES
proteins. These complexes take up unfolded proteins into an
internal chamber for folding (Fig. 3.17). ATP hydrolysis drives
folding.
Chaperonins
16. Neurodegenerative Diseases
In neurodegenerative diseases
such as Alzheimer's disease and
transmissible spongiform
encephalopathy (mad cow),
insoluble misfolded proteins
accumulate in the brain in
pathological lesions known as
plaques, resulting in
neurodegeneration (Fig. 3.18).
In Alzheimer's disease, the
protein known as amyloid
precursor protein is cleaved into
a peptide product (b-amyloid)
that aggregates and precipitates
in amyloid filaments. The
misfolding of b-amyloid, which
involves a transition from a
helical to b sheet conformation
leads to filament formation. In
mad cow disease, prion proteins
precipitate causing lesions.
17.
18. Ligand-binding Proteins
The term ligand refers to any molecule that can be bound by a
protein. Ligands may be hormones, metabolites, or even other
proteins. Ligand binding requires molecular complementarity. The
greater the degree of complementarity, the higher the specificity
and affinity of the interaction. Affinity is reflected in the Kd for
binding. Protein-ligand binding is illustrated here for antibodies
(Fig. 3.19a). The complementarity-determining regions (CDRs) of
the antibody make highly specific contacts with epitopes in the
antigen (Fig. 3.19b).
CDR Epitope
(a)
19. Overview of Enzyme Catalysis I
Enzymes are proteins (a few are RNAs called ribozymes) that
catalyze chemical reactions within living organisms. Enzyme-
catalyzed reactions typically are highly specific, and rate
enhancements of 106-1012 are common. In an enzyme-catalyzed
reaction, the reactant (the substrate) is converted into the
product. Like all catalysts, enzymes are not consumed in a
reaction. Further, they do not change the ∆G0' or Keq for the
reaction, only its rate.
Rate enhancement is
achieved due to the
fact that enzymes are
most complementary to
the transition state
structure formed in
the reaction. This
results in stabilization
of the transition state
and lowering of the
activation energy
barrier (∆G‡) for the
reaction (Fig. 3.20).
20. Overview of Enzyme Catalysis II
The transformation of a substrate to the
product occurs in the active site of an
enzyme. The active site can be subdivided
into a catalytic site wherein amino acids
that catalyze the reaction reside, and a
binding pocket that recognizes a specific
feature of the substrate, conferring
specificity to the enzyme-substrate
interaction. A schematic model for an
enzyme catalyzed reaction is shown in Fig.
3.23. The kinetic equation describing the
reaction E + S ES E + P. A reaction
coordinate diagram showing the binding and
catalytic steps of an enzyme catalyzed
reaction is shown in Fig. 3.24.
21. Enzyme Kinetics: Enzyme Concentration
The velocity of an enzyme-catalyzed reaction reaches a maximal
rate (Vmax) at high concentrations of substrate (Fig. 3.22a). Vmax
is achieved when all enzyme molecules have bound the substrate
and are engaged in catalysis (saturation). The French
mathematicians Michaelis and Menten developed a kinetic
equation to explain the behavior of most enzymes. They showed
that the maximal rate of an enzyme-catalyzed reaction (Vmax)
depends on the concentration of enzyme (Fig. 3.22a) and the
rate constant for the rate-limiting step of the reaction.
MM equation:
Vmax [S]
[S] + KM
V0 =
x
x
x
x
1.0
0.5
22. Enzyme Kinetics: Substrate Affinity
Michaelis and Menten also derived a kinetic constant, the
Michaelis constant (KM), that is indicative of the affinity of most
enzymes for their substrates. The lower the KM the higher the
affinity of the enzyme for the substrate (Fig. 3.22b). The KM
happens to be the concentration of substrate at which the
reaction rate is half-maximal. The concentrations of cellular
metabolites usually are set near the KMs of the enzymes that
carry out their metabolism. This allows cells to respond to
changes in substrate concentration.
1/2 Vmax
23. Mechanism of Serine Proteases I
Proteases are enzymes that cleave peptide bonds in other
proteins. The serine proteases, which are important for
digestion and blood coagulation, contain reactive serine residues
in their catalytic sites. Also present are aspartate and
histidine residues that together with serine make up what is
called the catalytic triad. The active sites of serine proteases
also contain binding pockets that confer specificity by
positioning the peptide bond that is to be cleaved next to the
reactive serine (Fig. 3.25a, trypsin). The digestive proteases
trypsin, chymotrypsin, and elastase select cleavage sites based
on the features of their binding pockets (Fig. 3.25b).
Specificity
Trypsin-basic aas
Chymotrypsin-aromatic aas
Elastase-small side-chain aas
24. Mechanism of Serine Proteases II
In the serine protease reaction mechanism, an acyl enzyme
intermediate is formed transiently after peptide bond cleavage
by serine (Fig. 3.26). Subsequently, the acyl group is hydrolyzed
off the serine later in the reaction. Both acid-base catalysis
(Steps a,c,d,& f) and transition state stabilization (Steps b & e)
occur during the reaction. The reaction mechanism is inhibited at
low pH due to protonation of His-57 (inset). The pH optimum of
serine protease reactions therefore occurs at or slightly above
neutrality.
25. Multifunctional Enzymes
Most metabolic pathways occur
via multiple enzyme-catalyzed
steps. As illustrated in Fig.
3.28, the rates of pathway
reactions can be increased if
the substrates and products
of each step are channeled to
the next enzyme in the
pathway. Channeling is
enhanced in multisubunit
enzyme complexes and by
attachment of enzymes to
scaffolds (Fig. 3.28b), or
even by fusion of encoded
enzymes into a single
polypeptide chain (Fig. 3.28c).
26. Regulating Protein Function by Degradation
The proteolytic degradation (turnover) of proteins is important for
regulatory processes, cell renewal, and disposal of denatured and
damaged proteins. Lysosomes carry out degradation of endocytosed
proteins and retired organelles.
Cytoplasmic protein degradation
is performed largely by the
molecular machine called the
proteasome. Proteasomes
recognize and degrade
ubiquinated proteins (Fig.
3.29). Ubiquitin is a 76-amino-
acid protein that after
conjugation to the protein,
targets it to the proteasome.
In ATP-dependent steps, the
C-terminus of ubiquitin is
covalently attached to a lysine
residue in the protein.
Polyubiquitination then takes
place. The proteasome
degrades the protein to
peptides, and released ubiquitin
molecules are recycling.
27. Regulating Function by Ligand Binding
The binding of a ligand to a
protein typically triggers an
allosteric ("other shape")
conformational change resulting
in the modification of its
activity. An overview of
regulation via allosteric
transitions is presented here in
the context of the tetrameric
O2 binding protein, hemoglobin
(Hb). As shown in Fig. 3.30,
the O2 binding curve for Hb
does not show the simple
hyperbolic shape exhibited by
proteins that bind a ligand with
the same affinity regardless of ligand concentration. Instead,
the Hb O2-binding curve is sigmoidal which indicates that the
affinity for O2 molecules increases after the first 1 or 2 have
bound. In this case, binding displays positive cooperativity.
Negative cooperativity is observed with other protein-ligand
systems. The reduced O2 binding affinity of Hb at low O2
tensions favors release of O2 to peripheral tissues.
28. Calmodulin-mediated Switching
Many proteins play switching
functions in cell signaling. Calcium
ion (Ca2+) is a very important
messenger in cell signaling. Cells
maintain cytoplasmic calcium
concentration at about 10-7 M.
When calcium concentration rises
above this level due to hormone-
receptor signaling processes, etc.,
it binds to a protein known as
calmodulin (Kd = 10-6 M) triggering
conformational changes that result
in its activation. Calmodulin
contains 4 helix-loop-helix motifs
(EF hands) each of which can bind
calcium (Fig. 3.31). Calcium
binding causes a major allosteric
transition in calmodulin. In its
alternate conformation, calmodulin
binds to target proteins, changing
their activity.
Ca2+
29. GTPase-mediated Switching
Proteins belonging to the GTPase superfamily, such as Ras and G
proteins, serve as guanine nucleotide-dependent regulatory
switches that control of the activity of specific target proteins
(Fig. 3.32). When bound to GTP, these proteins adopt an active
conformation that modulates target protein function. When bound
to GDP, their activity is turned off. The time-frame of activation
depends on the intrinsic GTPase activity (the timer function) of
these proteins. In addition, GTP and GDP binding (and thus
activity) may be regulated by other factors. Examples of such
regulation will be covered later.
Target protein
function
30. Regulation by Kinase/Phosphatase Switching
Protein function also can be regulated by allosteric transitions
caused by covalent modification via phosphorylation (Fig. 3.33).
Phosphorylation typically occurs on serine, threonine, and tyrosine
residues. Enzymes known as kinases carry out phosphorylation.
Their activity is opposed by phosphatases, which hydrolyze
phosphates off of the modified amino acid. Some proteins are
turned on by phosphorylation; others are turned off.