Otan sitaattina vielä netistä biologian opetusta prenylaatiosta, sillä SARS2-viruksella on muutamia interaktioproteiineja prenyloiduissa ihmisen proteiineissa kuten RAB14 ( Ras onkogeeni-perheen jäsen) , RALA( Ras like proto-onkogeeni A), RAB5C, RAB7A, RAB2A, RAB10, RHOA (Ras homologisen perheen jäsen A).
Prenylaatiotie taas on maailmassa yleisesti lääkkein vaikutettuna, koska sen tien päädyssä on koplesterolisynteesi, jota koetetaan säätää. Mitä lääkesäätö vaikuttaa prenylaation normaalikarttaan kehossa, on toinen asia. Prenylaatiotie on kompromittoitunut syövissä.
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https://what-when-how.com/molecular-biology/prenylation-molecular-biology/
Prenylation (Molecular Biology)
Prenylation or isoprenylation is a
post-translational modification (PTM) process in which cysteine residues close
to the C-terminal regions of some eukaryotic proteins are
biosynthetically modified with an isoprenoid lipid: the 15-carbon
farnesyl group or the 20-carbon geranylgeranyl group (see Fig. 1 and
Table 1). Prenylation provides some proteins with a hydrophobic membrane
anchor, and is important for their correct localization within the
cell. Prenylation is one of several processes that attach lipid membrane
anchors to proteins (see Membrane Anchors).
Figure 1. Modification of C-terminal cysteine residues by
prenyl groups. The C-terminal cysteine residue of the protein is
outlined by the dotted line. The thiol group is thioether-linked to
either a farnesyl or a geranylgeranyl group, and the exposed carboxyl
group is methylated.
http://what-when-how.com/wp-content/uploads/2011/05/tmp1C12_thumb.jpg
Table 1. Examples of Prenylated Proteins
Farnesylated
Ras proteins
Transducin g subunit
Rhodopsin kinase
Nuclear lamins A and B
Fungal mating pheromonesa
Geranylgeranylated
g subunits of heterotrimeric G-proteins
Ras-related G-proteins (
Rho/Rac/Rap/Ral/
Rab)
Isoprenoids are branched unsaturated hydrocarbons that
are synthesized in eukaryotic cells from
acetyl Coenzyme A (Acetyl CoA) by the first
part of the metabolic pathway that is used to synthesize cholesterol
and other sterols.
Attachment of isoprenoids to proteins is a
post-translational process with four main steps:
1) recognition of the
C-terminal sequence (
CAAX) by one of three distinct prenyltransferases (1);
2)
prenylation of a cysteine (
C) residue(s) located at or close to the
C-terminus using farnesylpyrophosphate (FPP) or geranylgeranylpyrophosphate (GGPP) as
the substrate;
3) proteolysis of the C-terminal residues (-AAX) exposes the
carboxyl group on the prenylated cysteine; and
4) the isoprenylated
cysteine is recognized by a
methyltransferase, which methylates the
carboxyl group using S-adenosyl methionine (SAM) as the methyl donor.
Steps 1)
to 3) take place in the
cytosol, whereas step 4) occurs on the
cytoplasmic surface of the
endoplasmic reticulum (ER) or the plasma membrane (PM) .
Thus efficient methylation requires prior isoprenylation to localize
the protein at the membrane surface. The thioether linkage between the
cysteine and the prenyl group is chemically
very stable and
probably not
subject to metabolic turnover. However, the carboxylic ester linkage to
the methyl group is relatively labile, and may be removed after
attachment. These steps differ substantially between proteins, depending
on the sequence motif at the C-terminus:
1. Cys-a-a-X (CAAX) If X is serine (S) , methionine (M), or
glutamine (E), it is recognized by
farnesyl transferase (FTase), and the cysteine
residue will be farnesylated.
If X is leucine (L), it is recognized by
geranylgeranyltransferase I (GGTase-1), and the cysteine residue will be
geranylgeranylated. The identity of the "a" residues (usually aliphatic)
is less important, but can influence whether isoprenylation takes place
or not.
Farnesyl transferase and geranylgeranyltransferase I are both
heterodimers; they have identical a subunits, whereas the a subunits
have only 30% identify.
Farnesylation can also occur at the C-terminus
of a variety of fungal mating pheromone peptides, and in yeast the same
enzyme is used for farnesylating both proteins and peptides. Although
farnesyl groups have relatively low affinity for membranes themselves,
they can enhance the membrane association due to other lipid groups.
Farnesyl groups, because of their small size, may also play an important
role in protein-protein interactions by binding directly to specific
sites on other proteins (2, 3).
2. Cys-Cys, Cys-X-Cys or Cys-Cys-X-X.
(CC, CXC or CCXX) These double
cysteine motifs (CC) are restricted to the
Rab subgroup of Ras-related small
G-proteins. The Rab protein first forms a complex with
Rab escort
protein (REP1, CHM).
The Rab-REP complex is then recognized by
geranylgeranyltransferase II.
After prenylation, REP remains bound to
Rab until it is delivered to the membrane.
REP (CHM) probably has a dual role:
recognition of Rab and masking the two geranylgeranyl groups until they
can be inserted into the appropriate membrane. Both cysteines are
geranylgeranylated, and consequently proteolysis cannot occur. The
C-terminus is not methylated in those Rab proteins ending with the
sequence Cys-Cys (4).
Many of the prenylated proteins are involved in signal transduction or vesicle traffic,
and the prenyl group, by facilitating rapid and reversible binding to
membranes, plays an essential role in these functions (5, 6).
The
membrane affinity of the prenylated proteins can be influenced by four
different mechanisms (for a general discussion of factors which can
affect membrane affinity of lipid anchored proteins, see Membrane
Anchors):
1. The attachment of a
palmitate residue (see
Palmitoylation)
to a cysteine close to the C-terminus reinforces the
binding (eg,
as in H- or N-Ras).
Palmitoylation only occurs in
membranes, however, so
prenylation is required for it to take place (7).
2. The presence of basic residues close to the
C-terminus will result in electrostatic attraction to the negatively
charged bilayer surface (as in K-Ras) and increase membrane affinity
(8).
3. Methylation converts the C-terminal residue from a
negatively charged, hydrophilic group to an uncharged, hydrophobic
group and increases membrane affinity approximately 10-fold (5, 6)). The
increase in affinity is due to the hydrophobicity of the methyl group,
rather than a reduction in electrostatic repulsion, because methylation
gives comparable increases in binding to uncharged membranes.
Methylation can have a profound influence on the cellular distribution
of farnesylated proteins, because the
farnesyl group is too short to
provide an effective anchor by itself. Turnover of the methyl group has
also been observed, and it is possible that repeated cycles of
methylation and demethylation are used to regulate protein function.
4. The membrane affinity will be reduced by soluble
carrier proteins, which are able to bind to the isoprenyl group(s) and
mask them from the aqueous environment. This mechanism is important for
the repeated releasing and recycling of Rab proteins during membrane
vesicular traffic processes (9, 10)).
