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Chapter01.lyx
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Chapter01.lyx
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#LyX 2.3 created this file. For more info see http://www.lyx.org/
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\begin_document
\begin_header
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\begin_body
\begin_layout Chapter
Proteins and cofactors
\begin_inset CommandInset label
LatexCommand label
name "chap:Proteins-and-cofactors"
\end_inset
\end_layout
\begin_layout Standard
A significant portion of organic compounds synthesized by living organisms
are biopolymers; proteins, lipids, nucleic acids, and other macromolecules
(e.g., lignins, gums, melanins).
Among these macromolecules, proteins fulfill key roles in almost every
biological process (catalysis, transport, mechanical-structural functions,
and others).
This extraordinarily rich diversity of functions is achieved despite the
fact that proteins are linear polymers built only of 20 types of canonical
amino acids
\begin_inset Foot
status collapsed
\begin_layout Plain Layout
Without taking into account
\begin_inset ERT
status open
\begin_layout Plain Layout
\backslash
glspl{ptm}
\end_layout
\end_inset
and amino acid residues that are inserted during the cotranslation process.
\end_layout
\end_inset
, those canonical amino acids linked sequentially into a linear polymer
are responsible for a staggering variety of folds, structures, and assemblies.
This gorgeous diversity of protein structures allows proteins to fulfill
an astonishing number of functions, however, not every chemical (or physical)
process is possible to conduct with only 20 canonical amino acids.
One way evolution
\begin_inset Note Note
status open
\begin_layout Plain Layout
nie wiem czy nie antropomorfizuję zbytnio ewolucji tutaj
\end_layout
\end_inset
has solved the problem of limited chemical groups that can facilitate important
processes is the use of
\begin_inset ERT
status open
\begin_layout Plain Layout
\backslash
glspl{cofactor}
\end_layout
\end_inset
and
\begin_inset ERT
status open
\begin_layout Plain Layout
\backslash
glspl{coenzyme}
\end_layout
\end_inset
.
Numerous publications state that roughly one-third of proteins interact
with
\begin_inset ERT
status open
\begin_layout Plain Layout
\backslash
glspl{cofactor}
\end_layout
\end_inset
\begin_inset Foot
status collapsed
\begin_layout Plain Layout
My duty to the reader is to point out that the statement that one-third
of proteins interact with
\begin_inset ERT
status open
\begin_layout Plain Layout
\backslash
glspl{cofactor}
\end_layout
\end_inset
is not very credible.
This type of statement often appears in various papers discussing the
\begin_inset ERT
status open
\begin_layout Plain Layout
\backslash
glspl{cofactor}
\end_layout
\end_inset
, yet one looks in vain for a reference to the literature or information
on what organism these proteins are from, or how the analysis was done.
\end_layout
\end_inset
\begin_inset CommandInset citation
LatexCommand citep
key "Rosenzweig2002,Bushmarina2006,Cao2011,frontiersin"
literal "true"
\end_inset
.
The
\begin_inset ERT
status open
\begin_layout Plain Layout
\backslash
gls{rcsb}
\end_layout
\end_inset
queried for structures of enzymes return over 30% of enzymes that contain
\begin_inset ERT
status open
\begin_layout Plain Layout
\backslash
glspl{cofactor}
\end_layout
\end_inset
, which points out that
\begin_inset ERT
status open
\begin_layout Plain Layout
\backslash
glspl{cofactor}
\end_layout
\end_inset
are essential for the functioning of a vast number of proteins
\begin_inset CommandInset citation
LatexCommand citep
key "Mukhopadhyay2019"
literal "true"
\end_inset
.
\begin_inset Note Note
status open
\begin_layout Plain Layout
coś o typie oddziaływania kofaktorów z białkami?
\end_layout
\end_inset
\end_layout
\begin_layout Standard
\begin_inset ERT
status open
\begin_layout Plain Layout
\backslash
Glspl{cofactor}
\end_layout
\end_inset
, contrary to the
\begin_inset ERT
status open
\begin_layout Plain Layout
\backslash
glspl{pgroup}
\end_layout
\end_inset
are not bound covalently to proteins, but associate with proteins by means
of other interactions, e.g., hydrogen bonds, Van der Waals forces, etc., thus
to interact with
\begin_inset ERT
status open
\begin_layout Plain Layout
\backslash
glspl{cofactor}
\end_layout
\end_inset
proteins had to evolve to form sites that will attract and associate with
\begin_inset ERT
status open
\begin_layout Plain Layout
\backslash
glspl{cofactor}
\end_layout
\end_inset
.
The residues (not the sequence!) that adopt particular conformation and
arrangement in space, being able to accommodate a particular
\begin_inset ERT
status open
\begin_layout Plain Layout
\backslash
gls{cofactor}
\end_layout
\end_inset
are called collectively a binding site.
\end_layout
\begin_layout Standard
Proteins are able to interact with organic, non-protein
\begin_inset ERT
status open
\begin_layout Plain Layout
\backslash
glspl{cofactor}
\end_layout
\end_inset
, called
\begin_inset ERT
status open
\begin_layout Plain Layout
\backslash
glspl{coenzyme}
\end_layout
\end_inset
, the inorganic molecules constituting
\begin_inset ERT
status open
\begin_layout Plain Layout
\backslash
glspl{cofactor}
\end_layout
\end_inset
are mostly metal ions.
The residues that binding sites that interact with metal ions are called
a
\begin_inset Quotes eld
\end_inset
metal binding sitea
\begin_inset Quotes erd
\end_inset
.
Among various
\begin_inset ERT
status open
\begin_layout Plain Layout
\backslash
glspl{cofactor}
\end_layout
\end_inset
, the Zn(II) cation is one of the most commonly found in proteins.
The
\begin_inset ERT
status open
\begin_layout Plain Layout
\backslash
glspl{mprotein}
\end_layout
\end_inset
interacting with Zn(II) are among the most diverse and widespread proteins
found in nature.
Genome sequencing projects have provided a great deal of information about
the structure of primary information about the primary structure of proteins.
The bioinformatic study of this information analyzed in terms of metal
interaction suggests that about 10% of the human proteome may bind Zn(II)
ions
\begin_inset CommandInset citation
LatexCommand citep
key "Andreini2006,Andreini2006a,Andreini2009"
literal "true"
\end_inset
.
What is worth noting is the fact, that those predictions (based solely
on the protein sequence) do not take into account the fact that the
\begin_inset ERT
status open
\begin_layout Plain Layout
\backslash
gls{L}
\end_layout
\end_inset
may be bound by two or more macromolecules.
This minuscule comment spans a variety of other, challenging questions
—
\begin_inset Quotes eld
\end_inset
How often this intermolecular metal binding is occurring?
\begin_inset Quotes erd
\end_inset
,
\begin_inset Quotes eld
\end_inset
What are the properties of such sites and the binding proteins?
\begin_inset Quotes erd
\end_inset
and many others.
\end_layout
\begin_layout Standard
This PhD project was dedicated to the analysis of proteins binding metal
ions in
\begin_inset ERT
status open
\begin_layout Plain Layout
\backslash
gls{ppi}
\end_layout
\end_inset
.
The part of the project realized
\emph on
in silico
\emph default
concerns the survey of all known proteins that bind metal ions in an intermolec
ular fashion (including zinc ion), while
\emph on
ex silico
\emph default
studies regard the interaction of metal ions with
\begin_inset ERT
status open
\begin_layout Plain Layout
\backslash
glsfirst{hs}
\end_layout
\end_inset
\begin_inset ERT
status open
\begin_layout Plain Layout
\backslash
gls{rad}
\end_layout
\end_inset
(See:
\begin_inset Flex CT - auto cross-reference
status open
\begin_layout Plain Layout
\begin_inset CommandInset ref
LatexCommand labelonly
reference "ch:Rad50"
plural "false"
caps "false"
noprefix "false"
\end_inset
\end_layout
\end_inset
).
\end_layout
\begin_layout Section
Metal ions
\end_layout
\begin_layout Subsection
Alkali and alkaline earth metal ions
\end_layout
\begin_layout Standard
Approximately 1% of the human body weight are made up of alkali and alkaline
earth metal ions
\begin_inset CommandInset citation
LatexCommand citep
key "Stephanos2014"
literal "true"
\end_inset
.
The role of alkali and alkaline earth metal ions in organisms is diverse,
sodium and potassium ions occur in all known organisms, and generally,
those ions function as electrolytes.
Calcium ions are known to function as messengers—used by living organisms
to communicate and orchestrate intracellular processes.
Magnesium ions are the most abundant divalent cations in the cell, the
majority of it bound to
\begin_inset ERT
status open
\begin_layout Plain Layout
\backslash
gls{atp}
\end_layout
\end_inset
, which is essential to utilize
\begin_inset ERT
status open
\begin_layout Plain Layout
\backslash
gls{atp}
\end_layout
\end_inset
\begin_inset CommandInset citation
LatexCommand citep
key "Schwartz2014"
literal "true"
\end_inset
.
\end_layout
\begin_layout Standard
\begin_inset Note Note
status open
\begin_layout Plain Layout
jeszcze coś o takim biologicznym aspekcie, co to robi w organiźmie itd.
\end_layout
\end_inset
\end_layout
\begin_layout Standard
In proteins both alkali and alkaline earth metal ions commonly play a structural
role in the stabilization of the
\begin_inset ERT
status open
\begin_layout Plain Layout
\backslash
gls{fold}
\end_layout
\end_inset
, however, those metals can play a catalytic role as well (e.g.
Mg(II) in T4 ligase
\begin_inset CommandInset citation
LatexCommand citep
key "Cherepanov2002"
literal "true"
\end_inset
).
Alkali and alkaline-earth compensate charge of highly acidic regions in
macromolecules, e.g., polyphosphate backbone in nucleic acids
\begin_inset CommandInset citation
LatexCommand citep
key "Owczarzy2004,Zheng2015,Varnai2004"
literal "true"
\end_inset
.
Despite the fact that the biology of alkali and alkaline earth metals is
quite well understood, it still hides some of the secrets, for instance,
the biological effects (as well as some of the side effects) of lithium
are known; lithium carbonate is widely used to treat some of the mood disorders
, however, the biological targets of Li(I) ions in the organisms are not
known yet.
\begin_inset Note Note
status open
\begin_layout Plain Layout
nwm czy tu trzeba cytacji
\end_layout
\end_inset
\end_layout
\begin_layout Standard
The alkali metals have a single
\emph on
s
\emph default
electron, and the alkaline earth metal ions have a filled outer
\emph on
s-
\emph default
orbital (by two electrons).
\begin_inset Note Note
status collapsed
\begin_layout Plain Layout
nwm czy poprawnie zapisany s oribal
\end_layout
\end_inset
Both groups of metals are highly electropositive and reluctantly polarizable
\begin_inset CommandInset citation
LatexCommand citep
key "Stephanos2014"
literal "true"
\end_inset
.
Due to the low polarizability alkali and alkaline earth metal ions are
considered to be a hard Lewis acid.
In accordance with Ralph Pearson's
\begin_inset ERT
status open
\begin_layout Plain Layout
\backslash
gls{hsab}
\end_layout
\end_inset
concept, hard Lewis acids should react more willingly with hard Lewis bases
\begin_inset CommandInset citation
LatexCommand citep
key "Pearson1963"
literal "true"
\end_inset
.
This behavior is easily confirmed by observation of the
\begin_inset ERT
status open
\begin_layout Plain Layout
\backslash
glspl{L}
\end_layout
\end_inset
that complex those metals, i.e., coordination sphere of those metal ions
is usually consisting of hard Lewis acids (in proteins, by oxygen-containing
acidic amino acids).
Usually alkali and alkaline-earth metal ions are coordinated by macromolecules
with six-coordinated octahedral geometry
\begin_inset CommandInset citation
LatexCommand citep
key "Kuppuraj2009"
literal "true"
\end_inset
, however more than six donor atoms are sometimes found in the alkali or
alkali-earth metal binding sites – mostly due to the bidentate
\begin_inset ERT
status open
\begin_layout Plain Layout
\backslash
glsdescplural{L}
\end_layout
\end_inset
\begin_inset CommandInset citation
LatexCommand citep
key "Zheng2008"
literal "true"
\end_inset
.
\begin_inset Note Note
status open
\begin_layout Plain Layout
moze przydałoby się tu wymienić co robią te pierwiastki?
\end_layout
\end_inset
\end_layout
\begin_layout Subsection
Transition metal ions
\begin_inset CommandInset label
LatexCommand label
name "subsec:Transition-metal-ions"
\end_inset
\end_layout
\begin_layout Standard
Transition metals are defined as elements that have partially filled
\emph on
d
\emph default
orbital.
Transition metals due to the fact that
\emph on
d
\emph default
orbitals are quite close in energy levels (degenerated), can form compounds
with a wide range of oxidation states, some of those states are quite stable.
The elements across the
\emph on
d
\emph default
block tend to be more polarizable.
Those two properties make the use of transition metals useful in catalysis,
thus there is no wonder why evolution has utilized so widely transition
metals in enzymes.
The first property is used when there is need for switching the oxidation
state of the enzyme's substrate.
In such enzyme, the metal ion can cycle between oxidation states and play
a role as an acceptor or donor of electrons (depending on the catalyzed
reaction).
The second property allow metal ions to function in the catalytic sites
without changing the oxidation state.
Such metal cations play a role of a Lewis acid, accepting pairs of electrons,
e.g., like Zn(II) in catalytic site of
\begin_inset ERT
status open
\begin_layout Plain Layout
\backslash
gls{ca2}
\end_layout
\end_inset
\begin_inset CommandInset citation
LatexCommand citep
key "Krishnamurthy2008"
literal "true"
\end_inset
.
\end_layout
\begin_layout Standard
In the presence of
\begin_inset ERT
status open
\begin_layout Plain Layout
\backslash
glsdescplural{L}
\end_layout
\end_inset
the orbitals of the transition metal ions break of degeneracy, this causes
a variety of physio-chemical effects (i.e., the property of having a color),
but also exerts a particular geometry of the complex.
Unsurprisingly proteins have evolved to accommodate a various geometries
of the metal ions—the metal binding sites have to match the geometry of
the particular metal ion to bind it.
\end_layout
\begin_layout Standard
Out of ten first-row transition metals, five of them are essential to human
health—manganese, iron, cobalt, copper and zinc (not being a transition
metal
\emph on
per se,
\emph default
discussed in
\begin_inset Flex CT - auto cross-reference
status open
\begin_layout Plain Layout
\begin_inset CommandInset ref
LatexCommand labelonly
reference "sec:properties_of_zinc"
plural "false"
caps "false"
noprefix "false"
\end_inset
\end_layout
\end_inset
).
The essentiality of those elements is nonnegotiable, as those elements
are
\begin_inset ERT
status open
\begin_layout Plain Layout
\backslash
glspl{cofactor}
\end_layout
\end_inset
or build some of the
\begin_inset ERT
status open
\begin_layout Plain Layout
\backslash
glspl{coenzyme}
\end_layout
\end_inset
of biologically important proteins or enzymes.
\end_layout
\begin_layout Standard
Manganese is present as a
\begin_inset ERT
status open
\begin_layout Plain Layout
\backslash
gls{cofactor}
\end_layout
\end_inset
in several enzymes, which maintain the metabolism, for examples in the
human bran manganese-dependent glutamine synthetase is responsible for
glutamine synthesis in astrocytes
\begin_inset CommandInset citation
LatexCommand citep
key "Takeda2003"
literal "true"
\end_inset
.
\end_layout
\begin_layout Standard
Iron accounts for 0.05‰ of human body weight.
Hemoglobin is a flagship protein that realizes the necessity of iron in
human diet.
Iron in
\begin_inset ERT
status open
\begin_layout Plain Layout
\backslash
glspl{mprotein}