Introduction to Bioorganic Chemistry and Chemical Biology
Answers to Chapter 9
(in-text & asterisked problems)
Answer 9.1
Names and acronyms from August 2011 issues of chemistry/biology journals are listed
below. The important point is that most of the papers in the current research literature
involve mysterious acronyms. The goal of this chapter is to familiarize you with those
acronyms that relate to signal transduction pathways that affect gene transcription in
humans.
Journal of Biological Chemistry 286, Issue 34 (2011)
Smad2/3 (a hybrid of C. elegans Sma (small) gene and Drosophila Mad (Mothers against
dpp) gene)
Hepatocyte Nuclear Factor 4α
RNA
Photosystem II (PSII)–Psb27 (photosystem protein b27) protein complex
ATP synthase
dentin matrix protein
integrin
MSH2 (DNA repair proteins homologous to yeast mutS/hexA)
Cdt2 (protein target of target of Cdc10 transcriptional regulation)
P21Waf1/Cip1 (kinase inhibitor protein 21 encoded by the Waf1/Cip1 genes)
VAMP8 (Vesicle-associated Membrane Protein 8)
SNARE (Soluble N-Ethylmaleimide-sensitive Factor Attachment Protein Receptor)
GSK3β (Glycogen Synthase Kinase-3β)
PTTG1/Human Securin (protein from Pituitary Tumor-Transforming Gene 1)
Myocyte Enhancer Factor 2C, an Osteoblast Transcription Factor
aurora-A
augmin
Hice1 Protein (Hec1-interacting and centrosome-associated 1)
microtubule
ARD1 (Arabidopsis Acireductone Dioxygenase 1)
Heterotrimeric G protein β subunit
Hsp90 (Heat-shock protein 90)
Immunophilin FKBP51 (FK-506 binding protein 51)
PSKs/TAOKs (Prostate-derived Sterile 20-like Kinases)
glucocorticoid
Dig2/RTP801/REDD1 (dexamethasone-induced Gene 2 Protein)
NKCC2 (bumetanide-sensitive Na+,K+,2Cl– Cotransporter)
Tamm–Horsfall protein
CaV1.3 channels (voltage-gated calcium channel 1.3)
c-Jun kinase (the Jun oncogene from Avian sarcoma virus was named after Ju nana, the
Japanese word for 17)
Runx2 protein (Runt-related transcription factor 2)
Escherichia coli DinD protein (DNA damage inducible protein D)
RecA (DNA recombinase A)
VAP-1 (Vascular Adhesion Protein-1)
oxime
acetylcholinesterase
1
2
Introduction to Bioorganic Chemistry and Chemical Biology: Answers to Chapter 9
cytochrome P450SPα (a heme enzyme that absorbs light at 450 nm)
fatty acid
autotaxin
Egr-1 protein (Early Growth Response 1)
HNF4α (Hepatocyte Nuclear Factor 4α)
SHP (Small Heterodimer Partner)
Mef2A transcription factor (myocyte enhancer factor 2A)
GRTH/DDX25 (Gonadotropin-regulated Testicular RNA Helicase)
StAR (Steroidogenic Acute Regulatory protein)
androgen receptor
TGF-β1 (Transforming Growth Factor-β1)
microRNA 143/145
TLR4 protein (Toll-like receptor 4)
MMP-1 (Matrix Metalloproteinase-1)
Chemical Biology 50, Issue 8 (2011)
retinal
mitochondrial Lon protease
docataxel tubulin
Hsp90 (heat shock protein 90)
JNK (Jun kinase)
Sab kinase (SH3 domain-binding protein that preferentially associates with Btk)
mycobacterial arabinosyltransferase
decaprenylphosphorylarabinose analogues
Kalata B1
Kir2 inward rectifier potassium channels (inwardly rectifying potassium channel 2)
RNA
Biochemistry 50, Issue 33 (2011)
p53 (mammalian tumor suppressor protein (53 kDa))
group 3 LEA protein (Late Embryogenesis Abundant)
nucleoplasmin
histone
prion
P. aeruginosa type III secretion translocators
P. aeruginosa heteromeric transmembrane pores
tyrosyl tRNA synthetase
nitric oxide synthase
Hsp70 (heat shock protein 70)
thioredoxin
rhodopsin
phoborhodopsin
prolyl–acyl carrier protein oxidase
P. aeruginosa isochorismate–pyruvate lyase
GTPase
chloroplast signal recognition particle
S100A4 (calcium-binding proteins soluble in 100% saturated ammonium sulfate)
myosin-IIA
mouse olfactory receptor
glmS riboswitch (glucosamine-6-phosphate activated ribozyme)
glucosamine 6-phosphate α-anomer
DNA polymerase
RNA
frataxin
cyclotide
GluA2 AMPA receptor (A2 ion channel receptor that binds to glutamate)
Introduction to Bioorganic Chemistry and Chemical Biology: Answers to Chapter 9
Science 333, August 11 (2011)
Fcγ receptor (receptor that binds to immunoglobulin constant fragment γ)
agonistic CD40 antibodies (complementarity determining/determinant 40)
Nature 476, Number 7360 (2011)
Lgr5 homologues (leucine-rich repeat-containing G protein-coupled receptor 5)
Wnt receptors (Wnt is a hybrid of the Drosophila Wingless gene and the mammalian
integration 1 gene)
R-spondin
histone
14-3-3 proteins
rice Hd3a florigen (heading date 3a)
MCU (mitochondrial calcium uniporter)
ribosome
Answer 9.2
Cycloheximide would have no effect since mucin release does not involve protein synthesis.
Physostigmine would enhance the effect of acetylcholine by preventing hydrolysis by
acetylcholinesterase.
Atropine would inhibit the rapid release of mucin by antagonizing the effect of acetylcholine.
Answer 9.3
Nuclear receptors and gas receptors.
Answer 9.4
The androgen receptor (AR) binds duplex DNA with the sequence AGGTCA; the estrogen
receptor (ER) binds to duplex DNA with the sequence TGTTCT. By connecting the DNAbinding domain of the androgen receptor to FKBP12 and the DNA-binding domain of
the estrogen receptor to mTOR, the two domains will dimerize and bind to DNA in the
presence of rapamycin. Semiflexible peptide linkers would be needed to connect the
domains; the C termini of FKBP12 and mTOR are closer together than the N termini.
5'-AGGTCANNNTGTTCT-3'
3'-TCCAGTNNNACAAGA-5'
AR
DBD
ER
DBD
5'-AGGTCANNNTGTTCT-3'
3'-TCCAGTNNNACAAGA-5'
rapamycin
AR
DBD
ER
DBD
FKBP12
mTOR
FKBP12
mTOR
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Answer
9.5
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The calculations suggest that roughly more than 1% of enone steroids exist as thiol
adducts, but Nature is cautious. The equilibrium constant for addition to steroid
enones such as testosterone is actually 100-fold less favorable (Keq = 0.02) than it is for
3-methylcyclohexenone.
3
4
Introduction to Bioorganic Chemistry and Chemical Biology: Answers to Chapter 9
1. How much adduct, x, is present at equilibrium?
K eq
HS
+
R'
R
O
[A]
O
R
R'
[A•R'SH]
[R'SH]
If thiol is depleted: 10-6 M - x
If thiol is not depleted: 10-6 M - x
S
thiol
adduct
0.005 M - x
0.005 M
x
x
2. Set up equations depending on your assumptions
If thiol is depleted:
If thiol is not depleted:
[A•R'SH]
K eq =
[A] [R'SH]
=
(x)
(10 -6 M - x)(0.005 M)
x
=
3. Plug in K eq
major
prednisone
adduct
R'
O
[A•R'SH]
[A] [R'SH]
=
(x)
(10 -6 M - x)(0.005 M - x)
... you end up with a quadratic equation; but since
[R'SH] >> [A], the answers you calculate, will not be
very different from the thiol depletion scenario
K eq
1
x
K eq
5x10-9 M2 - (0.005 M)• x =
x=
K eq =
(10 -6 M - x)(0.005 M)
5x10-9 M2
1
(0.005 M +
)
K eq
5x10-9 M2 - (0.005 M + 10-6 M +
O
progesterone
adduct
1
)•x + x2 = 0
K eq
O
S
O
less reactive
K eq ~ 7,000
S
R'
K eq ~ 2
M-1
x = 0.0097x10-6 M thiol adduct
0.990x10-6 M prednisone left over
x = 0.0099x10-6 M thiol adduct
0.990x10-6 M progesterone left over
99% of progesterone left over
99% of progesterone left over
Answer 9.6
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H435F,
H435K,
and H435R are too big and or
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too polar to form complementary interactions
with the bulky ethoxy group of QH2. H435G is probably too small and would leave empty space. The
H435A mutant is just right to complement the thyroid mimic QH2.
Answer 9.7
A IL-3, GM-CSF, IL-6, and IL-5
B IL-3, IL-7, IL-6, and IL-5
Answer 9.8
Most noncovalent interactions between small molecules and proteins have fast on-rates and reach
equilibrium very quickly. The fact that inhibition increases with longer incubation times and that the
sterically similar analog is inactive suggests a covalent reaction between stattic and STAT3, which has
numerous free cysteine residues. Cys712 (PDB 1BG1) makes contact with the active site and could
form an adduct with the vinylsulfone moiety.
Cys
-
O 2N
Cys
S
..
S
O O
S
O 2N
S
O O
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Introduction to Bioorganic Chemistry and Chemical Biology: Answers to Chapter 9
Answer 9.9
The extracellular environment favors disulfide formation. A cysteine residue stabilizes
the dimeric form of the receptor by forming a cystine disulfide crosslink.
R248C or
S249C FGFR3
monomers
dimer
D1
D1
D1
D2
D2
D2
C
D2
C C
C
D3
D1
D3
D3
D3
disulfide
bond
P
P
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Answer 9.10
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At a PD173074 concentration of 1000 nM, FGFR1, FGFR2, FGFR3, and VEGFR2 would be
more than 90% inhibited.
Answer 9.11
A FGFR, Shc1, MEK, ERK, and the transcription factor
B FGFR3 and Shc1
C FGFR3, Shc1, and ERK (which is activated through the phosphorylation of both threonine and tyrosine in its activation loop)
Answer 9.12
H
N
His
H N
-HO
3PO
-HO
3PO
His
H N
N+
H
H
O
H N
DAG
O
OP
H
H
O
O
+N
H
Arg
OH
N
N
H
salt bridge H
H
N
N+
H
-HO
3PO
H N
H
N
-
H
O
P
O O
HO3PO
-HO
3PO
OH
H
O
-
H
H
H
+N
N
H
N
H
Arg
His
N+
H
His
H
N
His
N
+
H
H
- ..O
HO
O
O
-HO PO
P
3
H
H
+N
O O
H
Arg
-HO PO
3
N
N
OH
H
H
H N
O
H
N
N+
H
.. DAG
HO
O O
O-HO PO
P
3
H
H
+N
O -O
H
Arg
-HO PO
3
N
N
OH
H
H
His
..N
N+
H
HO
H N
N+
H
-
His
N
His
DAG
O
OP
H
H
O
O
+N
H
Arg
OH
N
N
H
H
3PO
-HO
His
O:
HO
His
H
+ DAG
HO
O
O
O
-HO PO
P
3
H
H
+N
O -O
H
Arg
-HO PO
3
N
N
OH
H
H
H
N
His
N+
H
N:
HO
His
N+
H
5
6
Introduction to Bioorganic Chemistry and Chemical Biology: Answers to Chapter 9
H
N
His
H N
-HO
H
O
-HO
H N
H
O
OP
H
H
O
O
+N
H
Arg
OH
N
N
H
H
3PO
3PO
H
N
His
N+
H
N:
HO
His
N+
H
-HO
H N
H
O
OP
H
H
O
O
+N
H
Arg
OH
N
N
H
H
HO3PO
3PO
H
N
His
N+
H
..
O
HO
-
His
N+
H
N+
H
H
O
OP
H
H
..
+N
O -O
H
Arg
N
N
OH
H
H
HO
-HO
O
3PO
-HO
His
3PO
Answer 9.13
O
O
H
AcO
MeO
H
O
AcO
MeO
O
O
O
+
H
AcO
MeO
..
H2N
R
O
AcO
MeO
H A
O
H
O
+
H
O
:N R
H
O
O
OH
: A-
N
H + R
or...
O
H
etc.
AcO
MeO
H
O
O
O
AcO
MeO
+
OH
O
+
N R
H
: AH
H
O
O
H
O
O
O
AcO
MeO
O
H
AcO
MeO
H
O
H
O
O
O
an equally acceptable mechanism would involve...
O
O
H
O
O
O
H A
O
O
O
etc.
O
O
O
+
OH
H
AcO
MeO
O
O
:Nu
H A
O:
+
:Nu
O
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Answer
9.14
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AlF3 can form a non-hydrolyzable adduct with GDP that mimics GTP.
O
O
F
Al
FF
- OO O O
P
P
:O
O
O
N
O
HO
N
OH
NH
N
NH2
F - O O OF
O
Al
P
P
F - O
O
O
non-hydrolyzable
Introduction to Bioorganic Chemistry and Chemical Biology | A9151
Answer
9.15
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N
O
HO
N
NH
N
NH2
OH
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Because
forskolin activates
cyclase and a CB1 agonist reverses the effect of forskolin, it suggests that CB1 is coupled to Gαi,
an inhibitor of adenylyl cyclase. If the CB1 receptor is coupled to Gαi, the effect of Δ9-tetrahydrocannabinol would be inhibited by
pertussis toxin.
Introduction to Bioorganic Chemistry and Chemical Biology: Answers to Chapter 9
Answer 9.16
Various authors have suggested that aldehydes bind to the I7 odorant receptor as an
iminium ion (also known as a Schiff base), but there is no mechanistic evidence for or
against the hypothesis.
helix
4
K164
Y107
HO
helix
3
+HN
O
HO
O
-
D204
Y264
helix
5
helix
6
F205
F262
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Answer 9.17
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+
:
+
+
:
+
+
:
+
- ..
- ..
- ..
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Answer
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(From J.T. Gerig et al., J. Inorg. Biochem. 31:113–121, 1987. With permission from Elsevier.)
CO2N
O
OH
O
N
O
OH
O O
Ca
O O
O
N
O
O
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Answer 9.19
Van Vranken & Weiss | 978-0-8153-4214-4
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design by www.blink.biz of oligonucleotides in Chapter 3.
This
is similar to the photodeprotection
©
H
-O
O
N
+
O-
H
2C
-O
hν
RO
O N
O:
N
+
O-
2C
O N
OH
-O2C
O
R'
-A:
-O2C
H
O
N
O+
H
OO
-O2C .. N+
RO
RO
H A
-O2C
RO
O
:O N
-A:
-O2C
RO
OH
OH
+
O N
-O2C
O
O
..
R'
H A
O
O-O2C .. N+
H
O+O N
-O2C
..
H2O
O+
H
O N
O-
O N
-O2C
HO
OH
7
O N
O:
H A
O N
-O2C
RO
8
OH
:O N
-O2C
O
OH
OH
+
O N
-O2C
O
Introduction to Bioorganic Chemistry and Chemical Biology:
Answers
to Chapter
R'
R'
O
O +9
..
-A:
-O2C
or...
H
O
H
H A
O
O-O2C .. N+
ON
+
RO
O N
-O2C
HO
-O2C
..
H2O
O N
O-
-O2C
RO
RO
Introduction to Bioorganic Chemistry and Chemical Biology | A9155
Answer
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The product is undoubtedly
a conjugate addition product.
The stereochemistry at the
newly formed stereogenic center α to the carbonyl cannot be readily predicted without
knowledge of the interaction between kamebakaurin and the binding site.
O
OH
HO
:S
HO
O
OH
Cys
HO
H S
HO
Cys
OH
OH
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*Answer
9.23
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A Tyrphostin would inhibit all elements of these pathways.
B Wortmannin inhibits PI3K, the first enzyme in the apoptotic pathway.
C Rapamycin would selectively inhibit TOR and the effects on protein synthesis.
*Answer 9.25
R
R
hν
H
H
hν
H
H
HO
HO
photopyrocalciferol
R
R
>100°C
H
pyrocalciferol
H
H
H
HO
HO
precalciferol
calciferol
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*Answer
9.27
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The residues that contribute most significantly to binding are positively charged lysines
and arginines. It is therefore probably interacting with negatively charged aspartate or
glutamate residues on the receptor.
*Answer 9.29
There is some ambiguity in the P + 3 position, but on the basis of the intensity of the
spots, the best consensus sequence would be
*
XXPXYVNIR
The authors were cautious in their interpretation of preferences and counted only spots
that bound strongly to Grb2.
* I
XXXXYI
V NLX
V
*Answer 9.31
The simple way to do this is to load a suitably protected lysine onto an acid-labile resin
and then deprotect both the α-amino group and the side chain. Then one can perform
traditional solid-phase peptide synthesis using twice the normal amount of Fmocprotected amino acids. Finally the peptide can be cleaved under mild acid conditions.
acid cleavage: e.g.,
(Arg protected by Pbf or Pmc)
O
H2N
O O
NH2 O
H2N
O
H2N here
grow
O
NH2
NH
2
grow here
grow here O
H2N
O
NH2
grow here
1:1
O
acid cleavage:
e.g.,
CF 3CO2H/
(Arg protected
by Pbf or Pmc)
H
SPPS to Bioorganic(Arg
cleavage:
e.g.,
protected
by Pbf
or Pmc) Biology:acid
Introduction
Chemistry
and
Chemical
Answers
CH
1:1
2Cl2 to Chapter 9
N
1:1H/
O O
CF 3CO
2
H
SPPS
O
CO2H/
CF 3Cl
NH
CH
H
2
2
N
SPPS
-VPPPVPPRRR
X
H
N
X
CH
2
H2N-VPPPVPPRRR
Oacid2Cl2
N
acid cleavage: e.g.,
H2N-VPPPVPPRRR
O
(Arg protected by Pbf or Pmc) labile
NH
1:1
X
H2N-VPPPVPPRRR
NH acidX
H2N-VPPPVPPRRR
X 3CO2H/
X
O
CF
acidlabile
H
SPPS
CH2Cl2
labile
N
H2N-VPPPVPPRRR
O
NH
H2N-VPPPVPPRRR
X
acidH2N-VPPPVPPRRR
X
9
labile
The key challenge is how to deprotect the Nα and Nε amino groups without cleaving the amino acid from the resin. The authors
attached Nα-Fmoc-Nε-Fmoc lysine to a commercial Wang resin through a carbodiimide coupling and then removed the Fmoc
Wang linker
groups using piperidine/DMF.
O
O
HMB resin
FmocHN
H2N
O O Wang linker
HMB
H resin
Wang linker
O
HMB
resin
N
NH
piperidine H2N
FmocHN
O
OacidFmocHN Fmoc
H2N
H
O
O NH
labile
DMF
NH
piperidine
Fmoc
O
N
NH acidpiperidine
Wangacidlinker
Fmoc
OHMB resin
O
O
labile
DMF
O
labile
DMF
FmocHN
H2N
O
H
N
NH
piperidine
Fmoc
O
acidO
labile
DMF
O O
NH2 O
O
O
NH2
NH2
O
SPPS
SPPS
H
O NH
O
N
O
O
O
O
NH2
SPPS
H
N
O
SPPS
H
N
O
O
Alternatively one could attach the first amino acid to acid-labile chlorotrityl resin and follow the same sequence of steps as with
the Wang resin.
Grb2 peptidimer ligand
H
Grb2 peptidimer
ligand CO2N
C-SH3
N-SH3
C-SH3
C-SH3
N-SH3
N-SH3
C-SH3
N-SH3
Grb2 peptidimer ligand
H2N-VPPPVPPRRR
H
NH
NHCO2CO2NH
Grb2 peptidimer
ligand
H2N-VPPPVPPRRR
NH
H2N-VPPPVPPRRR
H
N
CO2H2N-VPPPVPPRRR
NH
H2N-VPPPVPPRRR
H2N-VPPPVPPRRR
H2N-VPPPVPPRRR
N
H2N-VPPPVPPRRR
The least desirable solution (that would still work) would be to attach the very common Nα-Fmoc-Nε-Boc lysine to an acid-stable
resin such as Merrifield resin and then use TFA to cleave the Boc side chain without cleaving the benzyl ester linkage.
very acid-labile
H
H
O O NH
N
O
O
very acid-labile
O
O
H
N
O Merrifield resin
i) CF3 CO2 H
H2N
(remove Boc)
Merrifield resin
O O
Merrifield resin i) CF3 CO2 H
O
NH
H2N
CF3 CO
2H
ii) i)piperidine
Fmoc
(remove
Boc)
O not
H2N
(remove
Boc)
O
DMF
very
NH
(remove
Fmoc)
ii) piperidine
acid-labile
Fmoc
NH
not
ii) piperidine
Fmoc
O Merrifield
notresin
DMF
very
i)
CF
DMF
3 CO
2 H Fmoc)
very
(remove
acid-labile
H2N
(remove
Boc) Fmoc)
(remove
O acid-labile
veryOacid-labile
N
very acid-labile
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Introduction to Bioorganic Chemistry and Chemical Biology | A9162
Van Vranken & Weiss | 978-0-8153-4214-4
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O
O O
NH2 O
O
O
NH2
NH2
O
O
NH2
anhydrous
HF
anhydrous
SPPS
anhydrous
HF
SPPS
HF
SPPS
SPPS
anhydrous
HF
10
Introduction to Bioorganic Chemistry and Chemical Biology: Answers to Chapter 9
*Answer 9.33
high energy excited state
OMe
hν
OO
CO2+H
O+H
aromatic OMe
3N
..N
N ..
O .. O -
O
+H3N
2C
-O
O
N
JAK
OH
O
O
N
H
O
OOH
S
OH
S
O
SH
JAK
JAK
Introduction to Bioorganic Chemistry and Chemical Biology | A9166
Van Vranken & Weiss | 978-0-8153-4214-4
*Answer
9.37
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NH2
O
-O P OO
O
H
N
R
N
R'
H H
O
..
BNH2
O
R
O
-O P OO
O
H
..
N
R
N R'
H
O
-
N ..
H
H
B
H
N
N
H
R
O
N
H
H
N
R'
O
NH2
~
~
S
O
R'
R
NH2
S
H
N
:S
O
R'
O
R
O
N
H
H
N
R'
O
lysine
Introduction to Bioorganic Chemistry and Chemical Biology | A9168
Van Vranken & Weiss | 978-0-8153-4214-4
*Answer
9.39
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Me
Me
HO
Me
Me
synthetic
vitamin D2
(ergocalciferol)
OH
OH
liver enzyme;
kidney enzyme
HO
Introduction to Bioorganic Chemistry and Chemical Biology | A9170
Van Vranken & Weiss | 978-0-8153-4214-4
© www.garlandscience.com design by www.blink.biz
N+
NO2
free
glutamate
O
SH O O
O
OMe
Introduction to Bioorganic Chemistry and Chemical Biology | A9164
Van Vranken & Weiss | 978-0-8153-4214-4
www.garlandscience.com
design by www.blink.biz
*Answer
9.35
©
JAK
O
NO2
O-
2C
N
2C
OMe
N+
H
N
..
O
B H
+H3N
-O
H H
B:
NO2
:OCO2-
3N
OMe
N
-O
+H
NO2
N+
O-
O
NO2
H
H
+N
.. N+
O O- O CO2-
OMe
B:
NO2
+N
3N
+H3N
OMe
NO2
..
N
N
*
OMe
NO2
ligand for the
vitamin D receptor
N
O
O-