Pdfcoffee - PDF: Ltrece Química Orgánica Biológica 4º Grado en Química Facultad de Química Universitat de València

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ltrece
Química Orgánica Biológica
4º Grado en Química
Facultad de Química
Universitat de València
Reservados todos los derechos.

No se permite la explotación económica ni la transformación de esta obra. Queda permitida la impresión en su totalidad.
Introduction to Bioorganic Chemistry and Chemical Biology 1
Answers to Chapter 6
(in-text & asterisked problems)

Answer 6.1
Solve the equation.
Convert temperature in °C to K by adding 273.
Plug the numbers into ΔG = ΔH – TΔS.
m
Kassociation = e–ΔG/RT. er as
This is the equilibrium constant for association, so take the inverse:
co
Kd = 1/Kassociation.
eH w
Protein Protein ΔH ΔS Kd
o.
(kcal mol–1) (cal K–1 mol–1)
rs e
mutant TCR β S. aureus –15.8 –21 at 25 °C 9.6 × 10–8 M

ou urc
chain 8.2 enterotoxin C3
p67phox Rac•GTP –7.3 52 at 18 °C 1.7 × 10–6 M

complex
o
iso-1- iso-1-cc –2.6 18.5 at 25 °C 1.1 × 10–6 M

aC s
cytochrome c peroxidase
vi y re
Answer 6.2
Calculated using Kd = koff/kon:
ed d
Protein Small ligands kon (M–1 s–1) koff (s–1) Kd

stu
chymotrypsin proflavin 1 × 108 8300 8.3 × 10–5
creatine kinase ADP 0.2 × 108 18,000 9.0 × 10–4

is
G-3-P dehydrog. NAD+ 0.2 × 108 1000 5.0 × 10–5
lactate dehydrog. NADH 10 × 108 10,000 1.0 × 10–5

Th
alcohol dehydrog. NADH 0.3 × 108 9 3.0 × 10–7

ar
lysozyme (N-Ac-Glu)2 0.4 × 108 100,000 2.5 × 10–3

sh
ribonuclease 3ʹ-UMP 0.8 × 108 11,000 1.4 × 10–5
Protein Large ligands kon (M–1 s–1) koff (s–1) Kd
tRNASer tRNASer 2 × 108 11 5.5 × 10–8

synthetase
trypsin protein inhibitor 0.07 × 106 0.0002 2.9 × 10–9
insulin insulin 1 × 108 20,000 2.0 × 10–4
β-lactoglobulin β-lactoglobulin 0.00005 × 108 2 4.0 × 10–4
α-chymotrypsin α-chymotrypsin 0.000004 × 108 0.7 1.8 × 10–3
https://www.coursehero.com/file/37863525/Answers-to-Chapter-6pdf/
a64b0469ff35958ef4ab887a898bd50bdfbbe91a-4117954
2 Introduction to Bioorganic Chemistry and Chemical Biology: Answers to Chapter 6
Answer 6.3
When the concentration of NADH is 3 × 10–7 M, the ratio of bound to unbound alcohol
dehydrogenase is 1:1. From there, the ratio of bound to unbound enzyme can easily be
estimated at other concentrations of NADH.
× 10–7 M
KD = 3
bound unbound
+ NADH
enzyme•NADH enzyme
[NADH] [enzyme•NADH] : [enzyme]

3 × 10–6 M 10 : 1
Introduction to Bioorganic Chemistry and Chemical Biology | A6019
10–7
3 ×Van M & Weiss | 978-0-8153-4214-4
Vranken 1 : 1
www.garlandscience.com
3 ×©10–8 M design
1 by www.blink.biz
: 10
3 × 10–9 M 1 : 100
A When [NADH] = 3 μM, the ratio of bound to unbound enzyme is 10/11 ≈ 91%.
m
B When [NADH] = 3 nM, the ratio of bound to unbound enzyme is 1/101 ≈ 1%.
er as
co
eH w Answer 6.4

cancer cells
[Curcumin] Dead / Live Percentage
o.
(µM) viable
rs e
5.5 1 : 1 50
O OH
11
ou urc
2 : 1 33
MeO OMe
55 10 : 1 9.1
550 100 : 1 1.0
HO curcumin OH 5500 1000 : 1 0.10
o
Van Vranken & Weiss | 978-0-8153-4214-4

Curcumin has poor bioavailability. At an oral dose of 8 g of curcumin per day, the peak
© www.garlandscience.com design by www.blink.biz
aC s
serum concentrations of curcumin reach only 1.8 μM. Hypothetically, eating large
vi y re
quantities of curcumin might be effective for colorectal cancer in the GI tract, but not for
systemic cancers like leukemias.
Answer 6.5
ed d
A Galactose binds most tightly because it has the lowest Km; however, the affinities of
all three substrates are within a factor of two.
ar stu
B Galactose is isomerized more than 100 times faster than the other two substrates
on the basis of the kcat/Km values: galactose (3700 mM–1 s–1), glucose (13 mM–1 s–1),
xylose (20 mM–1 s–1).
is
C If the system is at equilibrium, when the concentration of glucose is 10 Km (340 mM),

the ratio of glucose–enzyme complex to free enzyme will be 10:1. In a typical mam-
Th
malian cell, the intracellular glucose concentration is less than 1 mM. Of course the
amount of free enzyme is likely to be small because galactose and other sugars can
occupy the enzyme active site.
sh
Answer 6.6
A The substrate with the lowest Km binds most tightly: LRRASLG.
B The substrate with the highest kcat is phosphorylated fastest (once it binds): LR-
RASLG.
C The relative rates of phosphorylation will be proportional to kcat/Km. LRRASLG is bet-
ter than LRAASLG by a factor of 1507.
Substrate Km (μM) kcat (s–1) kcat / Km (M–1 s–1)

LRAASLG 12200 8.7 0.00071
LHRASLG 804 19.8 0.0246
LRRASLG 31 33.1 1.07
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..
Introduction toHBioorganic
A Chemistry and Chemical Biology: Answers to Chapter 6 3
O OH +H O 2
.. Ala Ala .. Ala +
Ala NH2 N N N
H H H
Answer 6.7OHC OHC OHC
Because imine formation is fast and reversible, the following mechanism is reasonable. O
The mechanism for imine/iminium ion formation
OH was covered in Chapter
OH 2. OH
Ala + Ala Ala Ala
N N.. H A N N:
H O HOH +H2O H H
R SH
.. ..
Ala HO
.. Ala +H
.. 2O Ala + +
Ala NH2 N SR N SR N SR
O H H H
OH OHC HO
OHC OHC
Ala O
N: +
H Ala N OH Ala N OH Ala N OH
Ala + Ala Ala Ala
+ N
N HN N:
SRH R S H R S H : A- R S H
R SH
.. HO
.. +H2O +
O SR SR SR
OH HO
Ala
N: +
H Ala N Ala N Ala N
m
er as
+
H
SR R S R S : A- R S
co
The rate-determining step for this reaction has not yet been determined, making
eH w

it difficult to determine the ordering of the various steps. It has been proposed that
hemithioacetal formation precedes imine formation. Unfortunately, this proposed
o.
mechanism involves the formation of a benzylic cation that is destabilized by the ortho
rs e
imine substituent.
ou urc
many unstable cation

steps R R
N N +
.. R N
+H
2O
+
o
H
SCys SCys Cys S
aC s

vi y re
Van Vranken6.8
Answer & Weiss | 978-0-8153-4214-4
many
Carboxamide hydrolysis and β-elimination
unstable cationprevent quantitative isolation of Asn, Gln,
steps R Thr. R
Ser, Cys, and N N
..
+
+H
R N
Asn 2O
O O +
ed d
H NaOH H
N SCys NHSCys
2 Cys S
N -O
ar stu
Introduction
H to Bioorganic
100 °C Chemistry and Chemical Biology | A6118
O
© www.garlandscience.com design byOwww.blink.biz
NH2 O-
Gln
is
O NaOH O
H
N NH2
N -O
Th
H 100 °C
O O
H2N -O
Ser
sh
O NaOH O
H H
N -. N
N N .
H H 100 °C H O O
HO HO H
N O
N -O
Cys H
O NaOH O
H H
N -. N
N N .
H H 100 °C H
HS HS
Thr
O NaOH O O O
H H H
N -. N N O
N N . N -O
H H100 °C H H
HO HO

Answer 6.9
The enzyme uses two Zn2+ ions and an arginine to stabilize the serine alkoxide, the
alkoxide leaving group and the anionic phosphorane intermediate, but these are
omitted to simplify the problem.
.. -
O O- HO-
Ser - O: O O- Ser O
P
Ser O
P
O
P -O O
-O O -O O- O- -
R R RO
R
.. -
O O-
Ser O O Ser O Ser O- O O-
P P

P
- O O - :O - -O O -O O
H H H
Answer 6.10
m
er as
Prostromelysin cannot cleave itself, because Cys75 holds the inhibitory domain in place
by coordinating to the Zn2+ ion at the active site (see the rendering of prostromelysin
co
in Figure 6.48). Arylmercurials have a high affinity for sulfur. They coordinate to Cys75,
eH w
opening up the Zn2+ active site, which can then proteolytically cleave the inhibitory
domain.
o.
rs e
ArHg
ou urc
ArHg S
+ S
Ar-Hg
S Zn Zn Zn
o

aC s

vi y re
Answer 6.11
trapoxin peptide
O Ph
Ph
ed d
NH HN O
O
stu
N H HN
OH Zn2+ binding element
O N
H
O
is
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©Van design by www.blink.biz
Vranken & Weiss | 978-0-8153-4214-4
Answer 6.12
Th
If the two ligands bound with perfect cooperativity, the dissociation constant would be
the product of the two Kd values, namely 10–6 × 10–6 = 10–12 M.
ar
Answer 6.13
sh
-
Bn Bn
+ Me + Me
N N
B: H :
S - S
R R
B H
Bn
O
+ Me - .. Bn H Bn
N O O +
Me B: Me
+
: N H N
- S
R
S R S R
CO2Me CO2Me CO2Me

Me Me
R R
+ +
H Bn BnN H B BnN
O S S
a64b0469ff35958ef4ab887a898bd50bdfbbe91a-4117954 + :
-
Bn Bn
+ Me + Me
N N
B: H :
S - S
R R
B H
Bn
O
+ Me - .. Bn H Bn
N O O +
Me B: Me
+
: N H N
- S
R
S S
IntroductionRto Bioorganic Chemistry and
R Chemical Biology: Answers to Chapter 6 5
CO2Me CO2Me CO2Me
Me Me
R R
+ +
H Bn BnN H B BnN
O S S
+ Me HO .. - B: H O
-.. N
CO2Me CO2Me
S
R
CO2Me
Me
R
+
BnN
S Bn
- ..O O +
N Me
CO2Me CO2Me + :
- S
R
Answer
Van Vranken6.14
& Weiss | 978-0-8153-4214-4
O
m
O O
er as
Enz Enz Enz
O-
NH2 H2N: H O- H2N H : O-
co
NH2 +
O N N
eH w

- OH - OH - OH
HO3PO HO3PO HO3PO
o.
rs e
N Me N+ Me N+ Me
H H
ou urc
O Enz O Enz
Enz +
H N HN CO2-
o
H2N: O- O-
B: H : NH
N NH
aC s
- OH - OH - O-
vi y re
HO3PO HO3PO HO3PO
N+ Me N+ Me + N Me
H H H
Answer 6.15
ed d
A ({G/C}{A/C}T)6
ar stu
B {G/A}{T/C}G{G/C}{G/C}G{G/T}{T/C}G{G/T}{T/C}G{G/A}{A/C}G
C {G/C}{C/A}C{G/C}CGG{C/T}G{G/T}CGG{C/A}G
is
*Answer 6.16
A Chorismate binds more tightly because it has the lower Km.
Th
B Chorismate is also rearranged more quickly (after it binds) because it has the much
larger kcat.
C Overall, chorismate (kcat/Km = 207 mM–1 s–1) is a better substrate than the O-methyl
sh
analog (kcat/Km = 0.29 mM–1 s–1) by almost three orders of magnitude.
*Answer 6.17
A
OH
H O strained
N
reactive
O intermediate
O
Me
B OH
OH OH OH..
H O H O H H
O- O
N HN Enz N
https://www.coursehero.com/file/37863525/Answers-to-Chapter-6pdf/ HN Enz N N
O O O O O O HN Enz O
.. O O
O +H N O O +H N O
+H
Me 3 Me - 3 Me 3N O Me
H
B:
C
A
OH
H O strained
N
reactive
O intermediate
O
Me
B OH
OH OH OH..
H O H O H H
O- O
N HN Enz N HN Enz N N
O O O O O O HN Enz O
.. O O
O +H
O O +H
O
Me 3N Me - 3N Me
+H
3N O Me
H
B:
OH OH OH OH
.. O O
H - HN Enz H O- H H
N
O
N HN Enz N HN Enz N HN Enz
:O O O O
O O O O
O +H
O O O O O
H 3N H +H
3N O +H +H
H .. - 3N H O 3N
Cl Cl Cl
D Me Me Me Me
O O-
m
.. + .. +
er as
R N O O R N O O H2N O O H2N O O-
H H
non-fluorescent fluorescent
co
eH w

Lone pair donation of the amino group into the coumarin ring system favors a cross-conjugated, non-aromatic form. When
aminocoumarin is conjugated to a peptide as an amide, the amino lone pair donates more into the amide carbonyl than into the
o.
coumarin ring system.design by www.blink.biz
© www.garlandscience.com
rs e
ou urc
*Answer 6.20
A - Enz
HO2C HO2C HO2C
S
.. Enz Enz
o
AcAspGluVal H AcAspGluVal S AcAspGluVal S

N N N
aC s
H H H
O O-
.. OH
H B
vi y re
B - Enz
S Enz Enz
HO2C .. HO2C S HO2C S
O O O
ed d
CbzAspGluVal N CbzAspGluVal N - CbzAspGluVal N

N N naphth N .. N naphth N N naphth
ar stu
H H H
O O O
naphth naphth naphth
H B
C - Enz
S Enz Enz
is
HO2C .. HO2C HO2C

O S O S O
O
CbzAspGluVal N Bn CbzAspGluVal N Bn CbzAspGluVal N Bn
Th
N N N N N N
H H H
O Bn O Bn O OH Bn
O .. -
H B

sh

*Answer
© 6.22
www.garlandscience.com design by www.blink.biz
Ser Ser
O :O - O: O Ser
- O
O O O
N R N R NH
R O
Introduction to Bioorganic Chemistry and Chemical Biology: Answers to Chapter 6 7
*Answer 6.25
The wild-type enzyme processes aspartate 1.2 × 106 times faster. The R292D variant
exhibits reversed selectivity, favoring arginine. However, the R292 variant processes
arginine more than about 104 times slower than the wild-type enzyme processes
aspartate.
H NH2 O D292
K258 N
- NH2 +
NH2 O
HO3PO -
H
O
N
O NH2
N -O
D223 - H + OH

+H R386
O 2N N
H
*Answer
© 6.27
www.garlandscience.com design by www.blink.biz
Cinnabaramide A is a strained β-lactone, structurally similar to salinosporamide. The
m
nucleophilic threonine of the proteasome reversibly attacks the β-lactone.
er as
co
eH w
OH OH OH..
H O H O H O-
N N N
o.
O S NHAc O S NHAc O S
..
rs e
O NHAc
O CO2Me O CO2Me
C6H13 C6H13 - C6H13 CO2Me
ou urc
H
B:
OH OH
o
O
H
N
O - HN Enz H
N HN Enz
:O
aC s
O O O
O O O
vi y re
H +H OH
3N +H
C6H13 C6H13 3N

*Answer 6.28
A H H H
ed d
H
H
O N O H N N N
H O H N N
stu
N N H N N
N N
G N N N H
N A
N H O C N
H G O
is

B ©Although some of the
www.garlandscience.com codons
design below are susceptible to
by www.blink.biz C to A transversion, those
Th
mutations would be silent.

Lys (AAA, AAG)
ar
Met (AUG)
Glu (GAA, GAG)
sh
Gly (GGU, GGC, GGA, GGG)

Trp (UGG)
Ile (AUU, AUC, AUA)
Val (GUU, GUC, GUA, GUG)
STOP (UAG, UGA, UAA)
*Answer 6.30
One way to approach this problem would be to examine each of the five histidine
residues in neuropsin to see which one is close to an Asp and a Ser residue. The catalytic
triad involves residues Asp57, His102, and Ser195.
m
er as
co
eH w

o.
rs e
ou urc
o
aC s
vi y re
ed d
ar stu
is
Th
sh
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Copyright:

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pdfcoffee.

Química Orgánica Biológica

Reservados todos los derechos.

Reservados todos los derechos.

mutant TCR β S. aureus –15.8 –21 at 25 °C 9.6 × 10–8 M

chain 8.2 enterotoxin C3

p67phox Rac•GTP –7.3 52 at 18 °C 1.7 × 10–6 M

iso-1- iso-1-cc –2.6 18.5 at 25 °C 1.1 × 10–6 M

Protein Small ligands kon (M–1 s–1) koff (s–1) Kd

chymotrypsin proflavin 1 × 108 8300 8.3 × 10–5

creatine kinase ADP 0.2 × 108 18,000 9.0 × 10–4

G-3-P dehydrog. NAD+ 0.2 × 108 1000 5.0 × 10–5

lactate dehydrog. NADH 10 × 108 10,000 1.0 × 10–5

alcohol dehydrog. NADH 0.3 × 108 9 3.0 × 10–7

lysozyme (N-Ac-Glu)2 0.4 × 108 100,000 2.5 × 10–3

ribonuclease 3ʹ-UMP 0.8 × 108 11,000 1.4 × 10–5

Protein Large ligands kon (M–1 s–1) koff (s–1) Kd

tRNASer tRNASer 2 × 108 11 5.5 × 10–8

trypsin protein inhibitor 0.07 × 106 0.0002 2.9 × 10–9

insulin insulin 1 × 108 20,000 2.0 × 10–4

β-lactoglobulin β-lactoglobulin 0.00005 × 108 2 4.0 × 10–4

α-chymotrypsin α-chymotrypsin 0.000004 × 108 0.7 1.8 × 10–3

[NADH] [enzyme•NADH] : [enzyme]

A When [NADH] = 3 μM, the ratio of bound to unbound enzyme is 10/11 ≈ 91%.

Reservados todos los derechos.

Van Vranken & Weiss | 978-0-8153-4214-4

C If the system is at equilibrium, when the concentration of glucose is 10 Km (340 mM),

Substrate Km (μM) kcat (s–1) kcat / Km (M–1 s–1)

Reservados todos los derechos.

many unstable cation

Introduction to Bioorganic Chemistry and Chemical Biology | A6118

Introduction to Bioorganic Chemistry and Chemical Biology | A6119

Reservados todos los derechos.

Introduction to Bioorganic Chemistry and Chemical Biology | A6120

Van Vranken & Weiss | 978-0-8153-4214-4

CO2Me CO2Me CO2Me

Reservados todos los derechos.

HO3PO HO3PO HO3PO

© www.garlandscience.com design by www.blink.biz

analog (kcat/Km = 0.29 mM–1 s–1) by almost three orders of magnitude.

Reservados todos los derechos.

AcAspGluVal H AcAspGluVal S AcAspGluVal S

CbzAspGluVal N CbzAspGluVal N - CbzAspGluVal N

HO2C .. HO2C HO2C

Introduction to Bioorganic Chemistry and Chemical Biology | A6128

Van Vranken & Weiss | 978-0-8153-4214-4

Reservados todos los derechos.

Cinnabaramide A is a strained β-lactone, structurally similar to salinosporamide. The

Introduction to Bioorganic Chemistry and Chemical Biology | A6134

Introduction to Bioorganic Chemistry and Chemical Biology | A6135

mutations would be silent.

Gly (GGU, GGC, GGA, GGG)

Reservados todos los derechos.

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