Dihydrofolate reductase (DHFR) is capable of making one carbon moieties of various ates (i.e., methanol, formaldehyde, fgmate). Folic acid, a B vitamin, provides the critical

Biochemistry
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ISBN:9781319114671
Author:Lubert Stryer, Jeremy M. Berg, John L. Tymoczko, Gregory J. Gatto Jr.
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Chapter1: Biochemistry: An Evolving Science
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Question 3. Dihydrofolate reductase (DHFR) is capable of making one carbon moieties of various
oxidation states (i.e., methanol, formaldehyde, formate). Folic acid, a B vitamin, provides the critical
chemistry:
This type of chemistry is utilized in the synthesis of nucleotides. Methotrexate has a significantly
higher affinity (Kd ~ 50 pM) than folate for the enzyme and is used in cancer therapy to suppress
DNA synthesis of rapidly dividing cancer cells. What is a tempting reason for methotrexate having
such high affinity?
(b)
CH:
H2N.
CH2
CH,
N-C-H
NH2
C
2-Amino, 4-amino analogs of folic acid
R = H
R - CH, Amethopterin (methotrexate)
Aminopterin
Does your suggestion change when told that crystallography determined that methotrexate binds to
the protein with opposite orientation to folate? (two sentences should do it)
HN
Folate
NADPH + H
NADP"
N°H
Dihydrofolate
NADPH+H IN
I7 +daVN
Transcribed Image Text:Question 3. Dihydrofolate reductase (DHFR) is capable of making one carbon moieties of various oxidation states (i.e., methanol, formaldehyde, formate). Folic acid, a B vitamin, provides the critical chemistry: This type of chemistry is utilized in the synthesis of nucleotides. Methotrexate has a significantly higher affinity (Kd ~ 50 pM) than folate for the enzyme and is used in cancer therapy to suppress DNA synthesis of rapidly dividing cancer cells. What is a tempting reason for methotrexate having such high affinity? (b) CH: H2N. CH2 CH, N-C-H NH2 C 2-Amino, 4-amino analogs of folic acid R = H R - CH, Amethopterin (methotrexate) Aminopterin Does your suggestion change when told that crystallography determined that methotrexate binds to the protein with opposite orientation to folate? (two sentences should do it) HN Folate NADPH + H NADP" N°H Dihydrofolate NADPH+H IN I7 +daVN
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