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Aromatic amino acids are precursors to
plant lignins, hormones, and natural
products
• Lignin (rigid polymer in plants) from Phe
and Tyr
• Auxin (growth hormone indole-3-acetate)
from Trp
• Other extracts: spices (nutmeg, vanilla),
alkaloids (morphine), etc.
세균 D-form
결핵치료제
Amino acid racemase inhibitors: antibacterial drug
Biosynthesis of Auxin from Trp and
Cinnamate from Phe
5) Neurotransmitter (신경전달물질)의 생합성
① Tyr → DOPA
② Glutamate
PLP
PLP
Dopamine → Norepinephrine. → Epinephrine
부족 (파킨슨씨병) VS 과잉 (정신분열증)
간질발작
GABA : 억제성 신경전달물질 ⇒ 간질, 고혈압증의 치료
③ Trp → 5-hydroxytryptophan PLP serotonin (→→melatonin)
④ His
PLP
histamine : 혈관확장제 cf) cimetidine: antagonist, 위산분비 억제
▪ polyamines ⅰ) putrescine, spermidine, spermine
ⅱ) 역할 - 세포의 성장인자
- (+)charge로 핵산 안정화
- tumor marker : 암 진행시 putrescine을 생합성시키는
ornithine decarboxylase 활성
▪ Africa 수면병의 치료 :파동편모충(trypanosome)
1) 증상: 발열지속 → 사망
2) ornithine decarboxylase의 기전: ornithine + PLP
▪ DFMO (difluoromethylornithine)
ⅰ) 자살저해제
ⅱ) ornithine decarboxylase를 불활성화시킴
H2O
CO2
Schiff base
putrescine
H2O
Amino acid decarboxylation yields
neurotransmitters, inhibitors
• Decarboxylations often require PLP
• Trp yields catecholamines such as dopamine,
norepinephrine, and epinephrine
• Glu yields neurotransmitters -aminobutyrate
(GABA) and serotonin
• His yields the vasodilator and stomach acid
secretion stimulant Histamine
Biosynthesis of Some Neurotransmitters
H2 antagonist: cimetidine(tagamet)
6) NO의 생합성
① NO의 역할: 신경전달물질, 혈액응고, 혈압조절
② 생합성과정: Arg
NADPH
NADP+
O2
H2O
[Hydroxy Arg.]
⇒ NADPH의 의존적 반응
③ NOS의 종류
Cit + NO
½NADPH
½NADP+
O2
H2O
a) iNOS: inducible (염증)
b) bNOS: brain (기억력)
c) eNOS: endothelial (혈관확장)
 Nucleotide의 생합성과 분해
▪ nucleotide의 역할
ⅰ) DNA, RNA의 전구체
ⅱ) 화학E의 운반체: ATP, GTP
ⅲ) Coenzyme의 구성성분(NAD, FAD, S-adenosyl Met, Coenzyme A)
& 활성화된 생합성 중간체의 성분(UDP-Glucose, CDP-diacyl glycerol)
ⅳ) 세포의 2nd messenger: cAMP, cGMP
Arg is precursor for nitric oxide (NO)
• Mid-80’s discovery that pollutant NO
played important role in blood pressure
regulation, blood clotting, etc.
• Synthesized from Arg via nitric oxide
synthase using NADPH
– Enz similar to cyt P450 reductase
– Stimulated by interaction with Ca2+ and
calmodulin
Biosynthesis of Nitric Oxide
22-30 Biosynthesis of spermidine and spermine
Nucleotide Biosynthesis
• Nucleotides can be synthesized de novo from amino
acids, ribose-5-phosphate, CO2, and NH3
• Nucleotides can be salvaged from nucleobases
• Many parasites (e.g., malaria) lack de novo biosynthesis
pathways and rely exclusively on salvage
– Compounds that inhibit salvage pathways are
promising anti-parasite drugs
아프리카 수면병: trypanosome(파동편모충) 원생동물 감염 → 발열
Mechanism of ornithine decarboxylase reaction
원생동물에는 치명적
Difluoromethylornithine(DFMO)
Suicide inactivators
1) Nucleotide 생합성의 경로
① De novo pathway: amino acid, Ribose-5 phosphate, CO2, NH3를 전구체로 합성
② Salvage pathway: 유리염기, nucleotide를 재이용
2) Purine nucleotide의 생합성
① 전구체: PRPP (Phosphoribosyl Pyrophosphate)
②
Asp
N
formic
acid
C
CO2
N
N
N
Gln
<purine>
Gly
Gln
O
Asp
N
formic
acid
O
CO2
N
<pyrimidine>
3) Ribonucleotide의 deoxyribonucleotide 환원
DNA
RNA
deoxy의
dNDP:nucleotide
NDP:
Ribonucleotide S
reductase
S
RNA의
nucleotide
Ribonucleotide
reductase
HS
Glutaredoxin
HS
Glutaredoxin
GSSG
2GSH
FAD
NADP+
NADPH + H+
Glutaredoxin
reductase
NADPH + H+
S
S
SH
SH
SH
S
Thioredoxin SH Thioredoxin
S
thioredoxin
reductase
FADH2
NADP+
4) Ribonucleotide Reductase 억제: DNA 합성억제 ⇒ 항암효과
전자전달
4) dUMP → dTMP
① dTMP의 생성: Ribonucleotide reductase에 의해 촉매 (CDP→dCDP, UDP→dUDP)
②
dUMP
dTMP
dCTP
dUTP
Thymidylate
synthase
N5,N10-methylene
7,8-Dihydrofolate
tetrahydrofolate
Glycine
dUMP
PLP
“DHFR”
dTMP
NADPH + H+
NADP+
Serine
Tetrahydro
folate
*DHFR(dihydrofolate reductase)
⇒ DNA 합성조절 可 ⇒ 항암치료
Origin of Ring Atoms in Purines
Asp
C
N
formic
acid
CO2
Gly
N
formic
acid
N
N
Gln
De novo synthesis of purine
nucleotides: construction of
the purine ring of inosinate (IMP)
Construction
of IMP
Synthesis of AMP and GMP from IMP
Regulation of
Adenine and
Guanine
Biosynthesis in
E. coli
Carbamoyl phosphate synthetase II (cytosol)
Asp
Gln amidotransferase
Gln
O
Asp
N
O
CO2
N
<pyrimidine>
22-36 De novo synthesis of
pyrimidine nucleotides: biosynthesis
of UTP and CTP via orotidylate
Reduction of Ribonucleotides
to Deoxyribonucleotides
by Ribonucleotide Reductase
Structure of Ribonucleotide
Reductase
Proposed ribonucleotide reductase
mechanism involves free radicals
• Most forms of enzyme have two
catalytic/regulatory subunits and two radicalgenerating subunits
– Contain Fe3+ and dithiol groups
– Enz creates stable Tyr radical to abstract H from sugar
• A 3’-ribonucleotide radical forms
• 2’-OH is protonated to help eliminate H2O and
form a radical-stabilized carbocation
• Electrons are transferred to the 2’-C
Proposed mechanism for
ribonucleotide reductase
Ribonucleotide reductase has two
types of regulatory sites
• One type affects activity
– ATP activates, dATP inhibits
• Other type affects substrate specificity in order to
maintain balanced pools of nucleotides
– If ATP or dATP high  less specificity for adenine and
MORE specificity for UDP and CDP, etc.
– Enzyme oligomerizes to accomplish this change.
Regulation of Ribonucleotide
Reductase by dNTPs
Oligomerization of Ribonucleotide
Reductase when dATP Binds
dTMP is made from dUTP
• Roundabout pathway…
1. dUTP is made (via deamination of dCTP or by
phosphorylaton of dUDP)
2. dUTP  to dUMP by dUTPase
3. dUMP  dTMP by thymidylate synthase
- adds a methyl group from tetrahydrofolate
Thymidylate synthase is a target for some anticancer
drugs.
Biosynthesis of dTMP
Conversion of
dUMP to dTMP by
Thymidylate
Synthase
Folic acid deficiency leads to
reduced thymidylate synthesis
• Folic acid deficiency is widespread,
especially in nutritionally poor populations
• Reduced thymidylate synthesis causes
uracil to be incorporated into DNA
• Repair mechanisms remove the uracil by
creating strand breaks that affect the
structure and function of DNA
– Associated with cancer, heart disease,
neurological impairment
Catabolism of Purines:
Formation of Uric Acid
• Degradation of purines proceeds through
dephosphorylation (via 5’-nucleotidase)
• Adenosine is deaminated to inosine and then
hydrolyzed to hypoxanthine and ribose
• Guanosine yields xanthine via these hydrolysis and
deamination reactions
• Hypoxanthine and xanthine are then oxidized into uric
acid by xanthine oxidase
• Spiders and other arachnids lack xanthine oxidase
Catabolism of
Purines
Conversion of Uric Acid to Allantoin,
Allantoate, and Urea
Catabolism of Purines:
Degradation of Urate to Allantoin
O
H
N
HN
-
O
O urate
N
N
H
O2 + H 2 O
urate oxidase
H 2 O2
O
HN
O
N
OH
H
N
O 5-hydroxyisourate
N
H2O
spontaneous
or
catalyzed
H
+
CO2
O
NH2
O
H
N
N
N
H H H
O
allantoin
• Urate is oxidized into a 5-hydroxyisourate by urate oxidase
• Hydrolysis and the subsequent
decarboxylation of 5-hydroxyisourate yields allantoin
• Most mammals excrete nitrogen
from purines as allantoin
• Urate oxidase is inactive in humans
and other great apes; we excrete
urate
• Birds, most reptiles, some
amphibians, and most insects also
excrete urate
Catabolism of Purines:
Degradation of Allantoin
O
NH2
H
N
allantoin
O
N
N
H H H
O
H2O
allantoinase
+
H
O
O
NH2
NH2
O
N
H
H
allantoate
H2O
allantoicase
O
O
H
O
NH2
O
O
N
H
NH2
NH2
urea
O
H2N
2 H 2 O + 4 H+
urease
2 CO2
4 NH4+
ammonium cation
• Most mammals do not degrade
allantoin
• Amphibians and fishes hydrolyze
allantoin into allantoate; bony
fishes excrete allantoate
• Amphibians and cartilaginous
fishes hydrolyze allantoate into
glyoxylate and urea; many excrete
urea
• Some marine invertebrates break
urea down into ammonia
Catabolism of Thymine, a Pyrimdine
Purine and pyrimidine bases are
recycled by salvage pathways
• Free bases, released in metabolism, are reused
– Example: Adenine reacts with PRPP to form the
adenine nucleotide AMP
• Catalyzed by adenosine phosphoribosyltransferase
• Brain is especially dependent on salvage
pathways
• Lack of hypoxanthine-guanine
phosphoribosyltransferase leads to Lesch-Nyhan
Syndrome with neurological impairment, fingerand-toe-biting behavior
Purine nucleotide 합성의 salvage pathway (재이용 경로)
Excess uric acid seen in gout
• Painful joints (often in toes) due to deposits of
sodium urate crystals
• Primarily affects males
• May involve genetic under-excretion of urate
and/or may involve over-consumption of fructose
• Treated with avoidance of purine-rich foods
(seafood, liver) or avoidance of fructose.
• Also treated with xanthine oxidase inhibitor
allopurinol
Allopurinol inhibits xanthine oxidase
Many chemotherapeutic agents
target nucleotide biosynthesis
• Glutamine analogs: azaserine, acivicin
– Inhibit glutamine amidotransferases
• Fluorouracil
– Converted by salvage pathway into FdUMP,
which inhibits thymidylate synthase
• Methotrexate and aminopterin
– Inhibit dihydrofolate reductase (competitive
inhibitors)
Antibiotics also target nucleotide
biosynthesis
• Allopurinol, etc.
– Studied against African sleeping sickness
(trypanosomiasis) because the trypanosomes
lack enzymes for de novo nucleotide synthesis
• Trimethoprim –
– Inhibits bacterial dihydrofolate reductase but
binds human enzyme several orders of
magnitude less strongly
Azaserine and Acivicin, Inhibitors of
Glutamine Amidotransferases
Proposed mechanism for glutamine
amidotransferases
Chemotherapy Targets―Thymidylate
Synthesis and Folate Metabolism
요로감염 (antibiotics)
Anticancer agent
Thymidylate synthesis and folate
metabolism as targets of chemotherapy
fdUMP Inhibition of dUMPdTMP
Conversion
Nucleotide metabolism 대사의 주요 개념도
Chapter Summary
In this chapter, we learned:
• Some prokaryotes are able to reduce molecular nitrogen into
ammonia; understanding details of the nitrogen fixation is one of
the holy grails in biochemistry
• The 20 common amino acids are synthesized via difficult-toremember pathways from -ketoglutarate, 3-phosphoglycerate,
oxaloacetate, pyruvate, phosphoenolpyruvate, erythrose 4phosphate, and ribose-5-phosphate
• Nucleotides can be synthesized either de novo from simple
precursors, or reassembled from scavenged nucleobases
• Purine degradation pathway in most organisms leads to uric acid,
but the fate of uric acid is species-specific
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