生物化學(xué)-生化課件chapter

CHAPTER

29BIOSYNTHESIS

OF

NUCLEOTIDESNucleotides

play

key

roles

in

the

followingbiochemical

processes:Asactivated

precursors

of

DNA

and

RNA核酸前體Their

derivatives

are

activated

intermediates

in

manybiosyntheses,e.g.

UDP-Glc

and

CDP-DAG

and

S-AMet

活性中間物ATP

is

a

universal

currency

of

energy

in

biologicalsystems,GTP

powers

many

movements

ofmacromolecules能量通用形式Adenine

nucleotides

are

components

of

3

majorcoenzymes:NAD+,FAD,and

CoA輔酶As

metabolic

regulators,e.g.

cAMP

and

ATP

代謝調(diào)節(jié)物Nucleotides

are

synthesized

from

simple

building

blocks(de

novo

synthesis從頭

)

or

by

the

recycling

ofpreformed

bases

(salvagesynthesis節(jié)約利用途經(jīng))Purines

(Pur.)

and

pyrimidines

(Pyr.)are

bui e

novo

from

AA,FH4derivatives,

NH4+

and

CO2The

PR

moiety

of

ribonucleotides

comes

from

PRPP,an

activateddonorDeoxyribonucleotides

are

synthesized

by

reduction

ofribonucleotides(dNDP

from

NDP)Finally,dTMP

is

formed

by

methylation甲基化of

dUMP(UMP→dUMP→dTMP)Nucleotide ogs

are

valuable

drugs

in

the

treatment

ofcancers(P753),viral

infections,autoimmune

diseases,andgenetic

disorders

such

as

gout痛風(fēng)癥(P757)The

purine

ring

is

synthesized

from

AA,FH4

derivatives,

andCO2The

Pur

Ring

is

assembled

de

novo

from

severalsimple

precursors–

1.

Gly

(C-4,

C-5,

N-7)Asp

(N-1)Gln

(N-3,N-9)兩次–FH4

(C-2,C-8)兩次–

CO2

(C-6)PRPP

is the

donor

of

the

PR

unitof

nucleotides

(Nt)PRPP

provides

PR

portion

for

the

synthesis

ofPurand

Pyr

Nt,

just

as

for

that

of

TrpPRPP

is

synthesized

from

ATP

and

R-5-P,

which

isprimarily

formed

byPPPPRPP

synthetase

catalyzes

the

transfer

of

the

β-

γ

pyrophosphorylgroup

of

ATP

toC-1ofR-5-PPRPP

has

an

α-configuration

at

C-1,

the

activated

carbon

atom

α-構(gòu)型The

Pur

ring

is

assembled

on

PRThe

committed

step

in

the

de

novo

synthesis

of

Pur

Nt

is

theformation

of

5-phosphoribosylamine(5-磷酸核糖胺)from

PRPPand

Glncatalyzed

by

amido-phosphoribosyl

transferase

酰胺磷酸核糖轉(zhuǎn)移酶The

amide

group(酰胺基)from

Gln

displaces

the

PPi

group

attached

to

C-1of

PRPPThe

configuration

at

C-1

is

inverted

from

α

to

βin

this

reactionThe

resulting

C-Nglycosidic

bond

has

βconfigurationthat

is

characteristic

ofnaturally

occurring

Nt

β-構(gòu)型是天然存在的核苷酸中的糖苷鍵的構(gòu)型This

reaction

is

driven

forward

by

the

hydrolysis

of

PPiAMP

and

GMP

are

formed

from

IMPIMP,

the

product

of

the

de

novo

pathway,

is

the

precursor

of

AMP

and

GMPIMP→adenylosuccinate

腺苷琥珀酸→AMPThe

difference

between

AMP

and

IMP

is

the

substitution

ofan

–NH2

for

the

=O

at

C-6IMP→XMP

黃苷酸→GMPIn

the

conversions

of

IMP

into

AMP

and

GMP,acarbonyl(羰基)oxygen

atom

is

replaced

by

anamino

groupsimilarly,

in

the

synthesis

of

IMP—step

4;in

the

formation

of

CTP

from

UTP(P748);and

in

the

conversion

of

Cit

into

Arg

in

the

ureacycle(P635)The

commonmechanistic

theme

of

these

reactions

is

theconversion

of

the

carbonyl

oxygen

into

a

derivative

thatcan

be

readily

displaced

by

an

amino

group羰基氧→(含有磷酸基的衍生物)→氨基The

reaction

mechanism

for

replacement

of

acarbonyloxygen

by

an

amino

group

is

shown

by

Fig

29-8The

attacking

nitrogen

can

befrom

NH3,Gln

or

Asp(三者都有氨基),The

leaving

group

in

this

class

of

reactionscan

be

Pi,PPi

or

the

AMP(三者都有磷酸基)moietyPur

bases

can

be

recycled

by

salvage補(bǔ)救reactions

that

utilize

PRPPPur

Nt(嘌呤核苷酸)can

be

synthesized

from

thepreformed

bases

(formedfrom

the

hydrolytic

degradationof

NA

and

Nt)by

asalvage

reaction

節(jié)約利用途經(jīng)(反應(yīng))which

is

simpler

and

much

less

costly

than

thereactions

of

the

de

novo

pathwayIn

the

salvage

reactions補(bǔ)救途經(jīng)(節(jié)約利用途經(jīng)),the

PR

moiety

of

PRPP

is

transferred

to

a

Pur

toform

the

corresponding

NtTwo

salvage

enzymes

with

different

specificitiesrecover

Pur

basesAdenine

phosphoribosyl

transferase

腺嘌呤磷酸核糖轉(zhuǎn)移酶(APRT):Adenine+PRPP→AMP+PPiHypoxanthine-guanine

phosphoribosyltransferase

次黃嘌呤-鳥嘌呤磷酸核糖轉(zhuǎn)移酶(HGPRT):Hypoxanthine(or

guanine)+PRPP→IMP(or

GMP)+PPi.AMP,

GMP,

and

IMP

are

feedbackinhibitors of

Pur

Nt

biosynthesisThe

synthesis

of

Pur

Nt

is

controlled

by

feedbackinhibition

and

other

regulatory

mechanisms

at

severalsites5-phosphoribosyl-1-pyrophosphate

synthetase5-磷酸核糖-1-焦磷酸

酶,

the

enzyme

thatsynthesizes

PRPP,

is

partially

inhibited

by

Pur

NtThe

enzyme

is

not

totally

switched

off

when

Pur

areabundant

for

PRPP

is

also

a

precursor

of

Pyr

and

ofHisThe

committed

step

in

Pur

Nt

biosynthesis

is

theconversion

of

PRPP

into

phosphoribosylamine磷酸核糖胺by

Gln-PRPP

amidotransferase

谷酰胺PRPP酰胺基轉(zhuǎn)移酶This

key

enzymeis

feedback-inhibited

by

many

Pur

NtIt

is

noteworthy

that

AMP

and

GMP,the

final

productsof

the

pathway,are

synergistic

協(xié)同的in

inhibiting

theamidotransferaseInosinate

(IMP)(次黃苷酸)is

the

branch

pointin

thesynthesis

of

AMP

andGMPThe

reactionsleading

awayfrom

IMP

are

sites

offeedbackinhibitionAMP

and

GMP

inhibit

the

conversion

of

IMP

intoadenylosuccinate

腺苷琥珀酸and

IMP

into

XMP黃苷酸GTP

and

ATP

are

the

substrates

in

the

synthesis

of

AMPand

GMP

reciprocally

交互This

reciprocal

substrate

relation

tends

to

balance

the

synthesis

ofadenine

andguanine

Nt使兩種嘌呤核苷酸的 平衡In

E.coli,

mostof

t e

encoding

enzymes

of

the

denovo

pathway

are

coordina y

regulatedSpecifically,

their

transcription

is

blocked

by

the

purine

repressor(Pur

R)嘌呤阻抑蛋白,

a

DNA-bindingprotein,whenhypoxanthine

(次黃嘌呤)

andguanine

areabundant.

嘌呤↑→嘌呤阻抑蛋白與DNA結(jié)合→

阻斷轉(zhuǎn)錄→編碼從頭 嘌呤核苷酸的酶↓The

Pyr

ring

is

synthesized

fromcarbamoylphosphate

氨甲酰磷酸and

Aspthe

Pyr

ring

is

assembled and

then

linked

to

PR

toforma

Pyr

Nt,

in

contrast

with

the

reaction

sequence

in

the

denovo

synthesis

of

Pur

Nt

嘌呤核苷酸的 是在磷酸核糖(PR)的基礎(chǔ)上 嘌呤環(huán)(堿基);而嘧啶核苷酸的

則是先 嘧啶環(huán)(堿基),再加入磷酸核糖(PR).The

precursors

of

the

Pyr

ring

are

carbamoyl

phosphate

andAspThere

are

twomajor

differences

in

the

synthesis

ofcarbamoyl

phosphate

used

to

synthesize

Pyr

and

to

makeurea–

compartmentation:

(in

eukaryotes)

in

the

cytosol

(for

Pyr)

and

inmito

(for

urea),

respectively,

and

by

different

carbamoyl

phosphatesynthetase

區(qū)域不同(

酶不同)–

Gln

rather

than

NH4+

is

the

N

donor

inthe

cytosolic

synthesis

ofcarbamoyl

phosphate

氮供體不同Also,

N-acetylglutamate

does

not

serve

as losteric

activator

in

the

cytosolicsynthesis.(變構(gòu)激活劑需否)Gln+

2ATP+

HCO3

→

carbamoyl

phosphate+

2ADP+

Pi+

Glu—The

committed

step

in

the

biosynthesis

of

Pyr

is

the

formation

of

N-carbamoylaspartate

N-氨甲酰天冬氨酸

from

Asp

and

carbamoylphosphate 4C1N+

1C1N

=

5C2N=

4C2N(嘧啶環(huán))

+1C(側(cè)鏈羧基,后脫去)–

This

carbamoylation

氨甲?；痠s

catalyzed

by

Asptranscarbamoylase

天冬氨酸轉(zhuǎn)氨甲酰酶The

Pyr

ring

is

formed

in

thecarbamoylaspartatecyclization環(huán)化with

lossof

water

to

yielddihydroorotate(DHO,二氫乳清酸,由二氫乳清酸酶催化).Orotate(乳清酸)is

then

formedby

dehydrogenation

of

DHO(由二氫乳清酸脫氫酶催化).Orotate

acquires a

PR moiety

fromPRPP

to

form

a

Pyr

NtOrotate→orotidylate(OMP)(乳清苷酸)→UMPacquisition

of

a

PR

groupfrom

PRPP

to

form

a

Pyr

Nt,

thisreaction

is

driven

by

the

hydrolysis

ofPPiOMP

is

decarboxylated

to

yield

UMP,a

major

Pyr

NtPyr

biosynthesisin

higher

organisms

iscatalyzed

by

multifunctional

enzymesInE

.coli

6

enzymes

that

synthesizeUMP

from

simple

precursorsappear

to

be

unassociatedIneukaryotes,

by

contrast,

5

of

them

are

clustered

in

two

complexesOne

of

these

multifunctional

enzymes

was

discovered

whenculturedmammalian

cells

were

treated

with

N-(phosphonacetyl)-L-Asp

(PALA,

N-磷酸乙酰-L-天冬氨酸)

用抑制劑處理培養(yǎng)的哺乳細(xì)胞,發(fā)現(xiàn)(在克服抑制作用而繼續(xù)存活的細(xì)胞中)三種酶(Carbamoyl

phosphate

synthetase,

Asptranscarbamoylase,and

DHOase

)的濃度都(同時(shí))提高了100倍Carbamoyl

phosphate

synthetase,

Asp

transcarbamoylase,

and

DHOase

arecovalently

joined

in

a

single

240-kd

polypeptide

chainThis

multifunctional

enzyme

is

called

CADOrotate乳清酸PR

transferase

and

OMP

decarboxylase

are

also

associated

ineukaryotesMultifunctional

enzymes

also

mediate

the

synthesis

of

Pur

invertebrates

(step2+3+5;

6+7;

9+10)能相關(guān)Indeed,the

covalent

linkage

of

functionally

relatedenzymes

occurs

often

in

eukaryotes

真核生物的酶經(jīng)常共價(jià)連接在一起(在同一條多肽鏈上)–

The

mammalian

FA

synthase,

which

contains

7

enzymaticactivities

in

each

of

two

chains,

is

another

striking

exampleThe

clustering

of

enzymes

catalyzing

a

reaction

sequencehas

several

potential

advantagestheir

synthesis

is

coordinated

and

their

assembly

into

a

coherentcomplex

is

easily

assured協(xié)調(diào)side

reactions

are

minimized

as

substrates

are

channeledfromone

catalytic

site

to

the

next副作用少a

covalently

linked

multifunctional

complex

is

likely

to

be

morestable

than

one

formed

by

noncovalent

interactions穩(wěn)定Multifunctional

enzymes

probably

evolved

by

exonshuffling外顯子改組Nucleoside

(Ns)

mono-,

di-,

and

triphosphatesare

interconvertibleThe

active

forms

of

Nt

in

biosynthesis

and

energyconversions

are

NDP

and

NTPconversion

of

NMP

to

NDP

is

catalyzed

byspecific

nucleoside

monophosphate

kinase

核苷單磷酸激酶

(1→2)–

that

utilize

ATP

as

the

phosphoryl

donore.g

:UMP+

ATP→UDP+

ADP;AMP+

ATP→2ADPNs

diphosphates

andtriphosphates

areinterconverted

bynucleoside

diphosphatekinase核苷二磷酸激酶,an

enzyme

that

has

broadspecificity(2→3)XDP+

YTP

→XTP

+

YDPXand

Y

can

be

any

ofseveral

ribonucleosidesor

deoxyribonucleosidesCTP

is

formed

by

aminationan

of

UTPboth

CTP

and

UTP

are

the

major

Pyr

ribonucleotides–

The

only

difference:

carbonyl

oxygen

at

C-4(UTP)

is

replacedbyan

amino

group(CTP)In

mammals,

amide

group

of

Gln

is

amino

donor,whereas

in

E.coli

NH4+

is

used

in

this

reactionMammals

avoids

having

a

high

level

of

NH4+inplasmaby

generating

it

in

situ

原位from

a

donorsuch

as

GlnATP

is

consumed

in

both

amination

reactionsAs

in

the

conversions

of

IMP

to

AMP

and

GMP,an

acyl

phosphate

intermediate?；姿嶂虚g物

is

nucleophilically親核

attacked

bya

nitrogenatomPyr

Ntbiosynthesis

inbacteria

isregulatedby

feedback

inhibitionThe

committed

step

in

Pyr

Ntbiosynthesis

in

E.coli

istheformation

of

N-carbamoylaspartatefrom

Asp

and

carbamoylphosphateAspartate

transcarbamoylase(ATCase),

the

enzyme

thatcatalyzes

this

reaction

is

feedback-inhibited

by

CTP,

the

final

productin

the

pathwayA

second

control

site

is

carbamoylphosphate

synthetase,

which

isfeedback-inhibited

by

UMPRibonucleotide

redu e

核苷酸還原酶,aradical

基enzyme,catalyzes

thesynthesisof

deoxyribonucleotides脫氧核苷酸dNt

are

the

precursors

of

DNA,that

are

formedbythereduction

of

ribonucleotides–

The

2’-hydroxyl

group

on

the

ribose

moiety

is

replacedby

ahydrogen

atomsubstrates

are

ribonucleoside

diphosphates

ortriphosphates

(ND TP),

and

ultimatereductant

is

NADPH:

NDP→dNDPThe

electrons

from

NADPH

are

transferred

to

thesubstrate

through

a

series

of

carriers:a

flavin黃素the

sulfhydryls巰基of

a

smallproteina

pair

ofirons

that

generate

atyrosyl

radicaland

then

another

pair

of

sulfhydrylsRibonucleotide

redu e

catalyzes

the

final

stage:The

substrate

specificity

and

catalyticactivity

of

ribonucleotide

redu e

areprecisely

controlledThere

are

twoallosteric

sitesin

ribonucleotide

redu e:

oneforoverall

activity(1),

another

for

substrate

specificity(2,3,4)NDP→dNDP

ATP+,dATP－(overall

catalytic

activity)

核糖核苷酸促進(jìn),脫氧核糖核苷酸抑制(脫氧核糖核苷酸的形成),以保持核糖核苷酸和脫氧核糖核苷酸之間的平衡UDP

(CDP)

→

dUDP

(dCDP)

dATP

or

ATP+(the

balance

between

Py

and Pu)嘌呤核苷酸(或脫氧嘌呤核糖核苷酸)促進(jìn)脫氧嘧啶核糖核苷酸GDP→dGDP

dTTP+ (the

balance

between

Py

and

Pu)脫氧嘧啶核糖核苷酸促進(jìn)脫氧嘌呤核糖核苷酸ADP→dADP dGTP+(the

balance

between

two

different

Pu

Nt)鳥嘌呤脫氧核糖核苷酸促進(jìn)腺嘌呤脫氧核糖核苷酸Thioredoxin

硫氧還蛋白and

glutaredoxin

谷氧還蛋白carry

electrons

to

ribonucleotide

redu

e(RR)Two

carriers

of

reducing

power

to

ribonucleotide

redu e

werefound—thioredoxin

and

glutaredoxinThe

process

ofthe

transfer

of

the

reducing

power(NADPH還原力→RR核糖核苷酸還原酶→ribose

unit底物)is

shown:NADPH→TR(FAD+TR)硫氧還蛋白還原酶→T硫氧還蛋白→RR→ribose

unitNADPH→GR(GR+FAD)谷氧還蛋白還原酶→G

谷胱甘肽→GX谷氧還蛋白→RR→ribose

unitDeoxythymidylate

(dTMP)

is

formedbymethylation甲基化

of

deoxyuridylate

(dUMP)uracil

is

not

a

component

of

DNA–

Rather,

DNA

contains

thymine,

the

methylated og

of

uracilthymidylate

synthase胸苷酸合酶catalyzes

this

finishing

touch:dUMP

is

methylated

todTMPThe

methyl

donor

in

this

reaction

is

a

FH4

derivative(N5,N10-methyleneFH4)

rather

than

S-A

MetThe

methyl

group

inserted

into

dTMP

is

more

reduced

than

themethylene

group

in

the

donorWhat

is

the

source

of

electrons

for

this

reduction?The

two

electrons

come

in

the

form

of

a

hydride

ion

(H－)from

the

FH4

moiety

itselfThishydrogen es

part

of

the

methyl

group

of

dTMPIn

this

reaction,FH4

is

oxidized

to

FH2.Thus

N5,N10-methylene

FH4

serves

both

as

an

electron

donor

and

as

aone-carbon

donor

in

the

methylation

reaction

既作為電子供體,又作為一碳單位供體We

see

here,

as

in

the

synthesis

of

Pu,

the

key

role

of

FH4derivatives.Indeed,

Nt

metabolism

and

AA

metabolism

are

closely

tied

byone-carbontransfer核苷酸代謝和AA代謝通過一碳單位轉(zhuǎn)移而密切連接Three-dimensional

structure

ofE.coli

dihydrofolateredu

ewith

a

bound

methotrexate.It

is

noteworthy

that

the

deoxyribose

and

thymineunits

of

DNA

are

formed

by

modification

ofribonucleotides

DNA中的脫氧核糖和胸腺嘧啶由RNA中的核糖核苷酸修飾后形成In

contrast,

no

known

ribonucleotide

is

formedfrom

adeoxyribonucleotideThese

precursor-product

relations

strongly

imply

thatribonucleotides

came in

evolutionThe

reactions

catalyzed

by

ribonucleotide

redu

eand

thymidylate

synthase

are

recapitulations(重述)ofthe

transition

from

aRNA

world

to

one

in

which

DNAbecame

the

store

ofgenetic

informationPotent

competitive

inhibitorsof

dihydrofolate

redu

eThe

anticancerdrugs

aminopterin氨基蝶呤(4-氨基葉酸)andmethotrexate氨甲蝶呤contain

an–

NH2

group

in

placeof

the

–OH

groupofdihydrofolate.Methotrexate

alsodiffers

in

having

a–CH3

group

insteadof

–H

atN10.Trimethoprim三甲氧芐二氨嘧啶,anantibacterialfolate

og.FH2

redu e

catalyzes

the

regenerationofFH4,

a

one-carbon

carrierFor

carrying

OCU,FH4

mustbe

regenerated

from

FH2that

is

produced

in

the

synthesis

of

dTMPThisis plished

by

FH2

redu e

using

NADPH

as

thereductant: FH2+NADPH+

H+

→FH4+

NADP+A

hydride

ion

is

directly

transferred

from

nicotinamide

ring

ofNADPH

to

pteridine

ring

of

FH2Several

valuable

anticancer

drugsblockthe

synthesis

of

dTMPRapidly

dividing

cells

require

an

abundant

supply

of

dTMP

forthesynthesis

of

DNAThe

vulnerability易受性of

these

cells

to

the

inhibition

of

dTMPsynthesis

has

been

exploited

in

cancer

chemotherapydTMP

synthase胸苷酸合酶

and

FH2

redu e二氫葉酸還原酶

arechoice

enzymesFluorouracil

氟尿嘧啶orfluorodeoxyuridine

氟脫氧尿苷,achemically

useful

anticancer

drug,is

converted

in

vivo

intofluorodeoxyuridylate(F-dUMP)This og

ofdUMP

irreversibly

inhibits

thymidylate

synthase

afteracting

as

a

normal

substrate

through

part

of

the

catalytic

cycle,

a

sulfhydryl

group

of

the

enzyme

adds

to

C-6

of

the

bound

F-dUMP-CH2-FH4

then

adds

to

C-5

of

this

intermediateInthe

case

of

dUMP,

a

hydride

ion

of

the

folate

is

subsequentlyshifted

to

the

–CH2-,

and

aproton

is

taken

away

from

C-5

of

theboundNtHowever,

F+

cannot

be edfromF-dUMP

by

theenzyme,and

so

catalysis

is

blocked

at

the

stage

of

the

covalent

complexformed

by

(1)

F-dUMP,(2)–CH2-FH4,

and(3)-SH

of

the

enzymeThis

is

an

example

of

suicideinhibition

抑制,

in

which

anenzyme

converts

a

substrate

into

a

reactive

inhibitor

thatimmedia y

inactivates

its

catalytic

activityThe

synthesis

of

dTMP

c so

be

blocked

by

inhibitingthe

regeneration

of

FH4

ogs

of

FH2,

such

as

aminopterin氨基蝶呤andmethotrexate

氨甲蝶呤,

are

potent

competitive

inhibitors(Ki

＜1nmol/L)

of

FH2

redu

eMethotrexate

is

a

valuable

drug

in

the

treatment

of

manyrapidly

growing

tumors,such

as

acu eukemia

andchoriocarcinoma

絨毛膜癌However,it

is

quite

toxic

because

it

killsrapidlyreplicating

cells

whether

they

are

malignant惡性or

not–

Stem

cells

inbone

marrow

骨髓,epithelial

cells上皮細(xì)胞of

theintestinal

tract,

and

hair

follicles毛囊are

vulnerable

to

theactionof

this

folateantagonist拮抗劑,accounting

for

many

of

its

toxicside

effectsFolate ogs

such

as

trimethoprim

三甲氧芐二氨嘧啶binds

105-fold

less

tightly

to

mammalian

FH2

redu

ethan

it

does

to

redu es

of

susceptible

microorganismsNAD+,

FAD,

and

CoA

are

formed

from

ATPNAD+:nicotinate

煙酸,或尼克酸→nicotinate

Nt煙酸核苷酸Nicotinate

is

derived

from

Trp.

Humans

can

synthesizethe

required

amount

of

it

if

the

supply

of

Trp

in

the

diet

is

adequateHowever,

an

exogenous

supply

of

it

is

required

if

thedietary

intake

of

Trp

is

lowA

dietary

deficiency

of

Trp

and

nicotinate

can

lead

topellagra

糙皮病,a

disease

charecterized

by

dermatitis

皮炎,diarrhea

腹瀉,and

dementia

癡呆Nicotinate

Nt→desamido-NAD+脫酰胺NAD+→NAD+NADP+

is

derived

from

NAD+

by

phosphorylation

of

the2’-hydroxyl

group

of

the

adenine

ribose

moiety–

This

transfer

of

a

phosphoryl

group

from

ATP

iscatalyzed

by

NAD+

kinaseFAD: riboflavin

核黃素

(VB2)→riboflavin5’-phosphate(orflavinmononucleotide)→flavinadenine

dinucleotide

黃素腺嘌呤二核苷酸Both

5’-phosphate

and

AMPunit

come

from

ATP,

so

2ATP

consumedhereCoA:

the

AMP

moiety

of

CoA

also

comes

from

ATPpantothenate泛酸(+ATP)→4’-phosphopantothenate

4’-磷酸泛酸

(+Cys+ATP)→4’-phosphopantothenyl

cystein4’-磷酸泛酰半胱氨酸(－CO2)→4’-phosphopantotheine

4’-磷酸泛酰巰基乙胺

(+ATP)→dephospho-CoA

脫磷酸CoA(+ATP)→CoAA

common

feature

of

the

biosyntheses

of

NAD+,FAD,andCoA

is

the

transfer

of

the

AMP

moiety

of

ATP

to

thephosphate

group

of

a

phosphorylated

intermediate

ATP將AMP(單位)轉(zhuǎn)移到磷酸化中間物的磷酸基上The

PPi

formedin

these

condensations

is

then

hydrolyzedto

PiAs

in

many

other

biosyntheses,

much

of

thethermodynamicdriving

force

comes

from

the

hydrolysis

of

the

released

PPiPu

in

humans

are

degraded

tourate尿酸The

Ntof

a

cell

undergo

continuous

turnoverNt

are

hydrolytically

degraded

to

Ns

by

nucleotidase

核苷酸酶Phosphorylytic

cleavage

of

Ns

to

free

bases

and

R-1-P

(ordeoxyribose1-P)

is

catalyzed

by

Ns

phosphorylases核苷磷酸化酶R-1-P

isisomerized

byphosphoribomutase磷酸核糖變位酶toR-5-P,a

substrate

in

the

synthesis

of

PRPPSome

of

the

bases

are

reused

to

form

Nt

by

salvagepathwaysAMP→IMP(脫氨，腺苷酸脫氨酶）→hypoxanthine

次黃嘌呤（水解除去磷酸，磷酸解切出核糖）→xanthine黃嘌呤→uricacid尿酸（以上兩步都由黃嘌呤氧化酶催化）In

humans,

urateis

the

final

product

of

Pu

degradation

and

isexcreted

in

the

urineGout

痛風(fēng)is

induced

by

high

serumlevels

of

urate尿酸Hyperuricemia

高尿酸血can

induce

gout,a

disease

thataffects

the

joints

and

kidneys–Inflammation

of

thejoints

is

triggered

by

the

precipitation

ofsodium

urate尿酸鈉crystalsMicrograph

of

sodium

urate

crystals.Gout

is

thought

to

be

an

inherited

metabolic

diseaseA

small

proportion

of

patients

with

gout

havea

partial

deficiency

ofhypoxanthine-guanine

phosphoribosyl

transferase

(HGPRT),

the

enzymecatalyzing

the

salvage

synthesis

of

IMP

and

GMPA

deficiency

of

HGPRT

leads

to

reduced

synthesis

of

GMP

and

IMP

bythe

salvage

pathwayThe

consequent

increase

in

the

level

of

PRPP

markedly

accelerates

Pubiosynthesis

by

the

de

novo

pathwayThe

formation

of

5-phosphoribosyl-1-amine,

the

committedintermediate,

is

normally

limited

by

the

availability

of

PRPPExcessive

PRPP

also

interferes

with

feedback

inhibition

of

theamidotransferase

轉(zhuǎn)酰胺酶that

catalyzes

this

stepHGPRT部分缺陷→節(jié)約利用途徑受阻→PRPP增加(變構(gòu)調(diào)控受損的高活性PRPP

酶也導(dǎo)致PRPP增加)→嘌呤從頭

加速

(限速酶活性升高)→嘌呤分解產(chǎn)物(尿酸)增多

→痛風(fēng)癥Gout

c so

result

from

excess

PRPP

produced

by

a

hyperactivesynthetase

高活性PRPP

酶having

impaired

allosteric

regulationog

of

hypoxanthine

isAllopurinol

別嘌呤醇,anextensively

used

to

treat

goutIts

mechanism

of

action

is

that

it

acts as

a

substrate

and

thenas

an

inhibitor

of

xanthine

oxidase先作為黃嘌呤氧化酶的底物,(經(jīng)催化改變)后作為此酶的“

”性抑制劑The

oxidase

hydroxylates

it

to

alloxanthine

別黃嘌呤,which

thenremains

tightly

bound

to

the

activesiteThe

molybdenum鉬atom

of

xanthine

oxidase

is

kept

in

the+4oxidation

state

by

the

binding

of

alloxanthine

instead

of

returningto

the+6

oxidation

state

as

in

a

normal

catalytic

cycleWesee

hereanotherexample

of

suicide

inhibition.

(anotherexample:5-Fu

orF-dUMP)

性抑制(原本不具抑制作用的底物經(jīng)酶的催化作用后與酶共價(jià)結(jié)合并使之立即失活,即酶‘

“.

別嘌呤醇—黃嘌呤氧化酶;

5-Fu

—胸苷酸合酶)The

synthesis

of

urate

from

hypoxanthine

and

xanthine

decreasessoon

after

the

administration

of

allopurinol.Hence,the

serum

concentration

of

hypoxanthine

and

xanthine

rise,whereas

that

of

urate

drops

中次黃嘌呤(和黃嘌呤)濃度升高,而尿酸濃度降低The

formationof

uric

acid

stones

is

virtually

abolished

by

allopurinol,and

thearthritis es

lesssevere.Also,

the

rate

of

Pu

biosynthesis

decreases

because

allopurinolsequesters

螯合PRPP

by

forming

the

NtFurthermore,allopurinolribonucleotide

inhibits

the

conversion

ofPRPP

intophosphoribosylamine別嘌呤醇抑制黃嘌呤氧化酶(減少尿酸的生成),螯合

PRPP(形成核苷酸)從而減少嘌呤的從頭

,此別嘌呤醇核苷酸抑制由PRPP(+Gln)生成5-磷酸核糖胺(限速步驟)Urate

plays

a

beneficial

role

as

apotent

antioxidantaverage

serum

level

of

urate

in

humans

is

close

tosolubility

limit

and

is

tenfold

higher

thanprosimians原猴類A

striking

increase

in

ura evel

occurred

in

theevolution

of

primates

靈長目What

is

selective

advantage

of

a

ura evel

so

highthat

it

teeters

on

the

brink

of

甘冒風(fēng)險(xiǎn)gout

in

manypeople?人類

中尿酸的濃度是原猴類的十倍,已接近其溶解度的極限(類似地,哺乳動(dòng)物血紅素降解的最終產(chǎn)物是膽紅素而不是膽綠素,它也存在溶解度低的問題)It

turns

out

that

urate

has

a

markedly