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Biochemistry > DNA: Nucleotide Metabolism > Flashcards

DNA: Nucleotide Metabolism Flashcards

0
Q

Universal energy currency in all cells. ____ also used.

A

ATP. GTP.

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1
Q

Participates in many biochemical reactions

A

Purines & Pyrimidines

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2
Q

3 major coenzymes

A

NAD+, FAD & Coenzyme A

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3
Q

Are components of 3 major coenzymes

A

Adenine Nucleotides

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4
Q

Are activated intermediates in many biosynthesis

A

Nucleotide derivatives

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5
Q

Biosynthesis: UDP to

A

Glucose to Glycogen

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6
Q

Biosynthesis: CDP to

A

Diacyglycerol to Phosphoglycerine

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7
Q

Are metabolic regulators

A

Nucleotides

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8
Q

2nd messenger in many hormone actions

A

cAMP

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9
Q

Are activated precursor in nucleic acid synthesis.

A

Nucleoside triphosphates

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10
Q

Critical reactions in ______ & ______ biosynthesis are target for cancer chemotherapy and viral disease treatment.

A

Purine & Pyrimidine.

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11
Q

In purine nucleotide synthesis, Purine Ribonucleotides formed ________. Purines are not initially synthesized as ______.

A

De novo. Free bases.

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12
Q

First purine derivative is

A

Inosine Mono-phosphate(IMP)

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13
Q

AMP & GMP are formed from

A

IMP

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14
Q

Enumerate the 10 biosynthetic steps in purine biosynthesis

A

“PAFNR CAFFR” *refer to handout

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15
Q

1st step in Purine Biosynthesis: ___ displacement by ___. Thru

A

PP. NH2. Glutamine.

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16
Q

2nd step in Purine Biosynthesis: addition of ________. Thru

A

Glycine. ATP + Glycine

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17
Q

3rd step in Purine Biosynthesis: ______ group transfer. Thru

A

Formyl. N10Formyl THF

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18
Q

4th step in Purine Biosynthesis: ___ transfer. Thru

A

NH2. ATP + Glutamine

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19
Q

5th step in Purine Biosynthesis: _____ closure. Thru

A

Ring. ATP.

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20
Q

6th step in Purine Biosynthesis: ______ addition. Thru

A

COO-. CO2

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21
Q

7th step in Purine Biosynthesis: _____ addition. Thru

A

Aspartate. ATP + Aspartate

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22
Q

8th step in Purine Biosynthesis: ________ loss. Thru

A

Fumarate. Fumarate

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23
Q

9th step in Purine Biosynthesis: _______ group transfer. Thru

A

Formyl. N10Formyl THF

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24
Q

10th step in Purine Biosynthesis: ring _______.

A

Closure

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25
Q

The activated sugar used in purine nucleotide synthesis is

A

5-phosphoribosyl-1-pyrophosphate “PRPP”

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26
Q

PRPP is generated by the action of __________ and requires energy in the form of ____. This action releases ____. Therefore , 2 high energy ______ equivalents are consumed during the reaction. First committed step in purine synthesis (regulated) Inhibited by ____ & ____ (allosteric)

A

PRPP synthetase. ATP. AMP. Phosphate. ADP & GDP.

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27
Q

The major site of purine synthesis

A

Liver

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28
Q

Synthesis of purine nucleotides begin with _____ and leads to the first fully formed nucleotide, ___________.

A

PRPP. Inosine 5’-monophosphate “IMP”

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29
Q

The purine base is built upon the ribose by several _________ & _______ reactions.

A

Amidotransferase. Transformylation.

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30
Q

The synthesis of IMP requires __ moles of ATP, __ moles of glutamine, __ mole of glycine, __ mole of CO2, __ mole of aspartate and __ moles of formate.

A
          1. 2.
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31
Q

The formyl moieties are carried on tetrahydrofolate (THF) in the form of ____________ and ___________.

A

N5, N10. Methenyl- THF and N10-formyl-THF.

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32
Q

Sources of atom in Purine Biosynthesis

A

Glycine, Glutamine, Aspartate, N5 N10 Methenyl THF, N10 Formyl THF & CO2. “GGANNC”

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33
Q

Synthesis of AMP/GMP: ___ represents a branch point of purine biosynthesis, because it can be converted into either ___ or ___ through two distinct reaction pathways.

A

IMP. AMP or GMP.

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34
Q

Synthesis of AMP/GMP: The pathway leading to AMP requires energy in the form of ___; that leading to ___ requires energy in the form of ___.

A

GTP. GMP. ATP.

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35
Q

Synthesis of AMP/GMP: allows the cell to control the proportions of AMP & GMP to near equivalence.

A

Utilization of GTP in the pathway to AMP

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36
Q

Synthesis of AMP/GMP: the accumulation of excess GTP will lead to accelerated ___ synthesis from ____ instead., at the expense of ___ synthesis.

A

AMP. IMP. GMP.

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37
Q

Synthesis of AMP/GMP: Conversely, since the conversion of IMP to GMP requires ATP, the accumulation of excess ATP leads to accelerated synthesis of ___ over that of ___.

A

GMP. AMP.

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38
Q

The essential rate limiting steps in purine biosynthesis occur at the

A

First two steps of the pathway

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39
Q

The synthesis of PRPP by PRPP synthetase is feed-back inhibited by

A

Purine-5’-nucleotides. (Predominantly AMP & GMP)

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40
Q

The amidotransferase reaction (2nd step) catalyzed by _________ is also feedback inhibited by binding ATP, ADP & AMP at one inhibitory site and GTP, GDP & GMP at another. Conversely the activity of the enzyme is stimulated by _____.

A

PRPP glutamyl amidotransferase. PRPP.

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41
Q

Purine biosynthesis is regulated in the branch pathways from IMP to AMP and GMP. The accumulation of excess AMP leads to accelerated synthesis of ___,and excess of this leads to accelerated synthesis of ___.

A

GMP. AMP.

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42
Q

Catabolism of the purine nucleotides leads ultimately to the production of _______ which is insoluble and is excreted in the urine as _________.

A

Uric acid. Sodium urate crystals.

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43
Q

The synthesis of nucleotides from the purine bases and purine nucleosides takes place in a series of steps known as the

A

Salvage pathways

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44
Q

The free purine bases _______, ______ & ______, can be converted to their corresponding nucleotides by ___________.

A

Adenine. Guanine. Hypoxanthine. Phosphoribosylation.

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45
Q

Two key transferase enzymes that are involved in the salvage of purines

A

Adenosine phosphoribosyltransferase(APRT) and Hypoxanthine-guanine phosphoribosyltransferase(HGPRT)

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46
Q

Hypoxanthine + PRPP IMP + PPi and Guanine + PRPP GMP + PPI. Catalyzed by

A

Hypoxanthine-guanine phosphoribosyltransferase(HGPRT)

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47
Q

Adenine + PRPP AMP + PPI. Catalyzed by

A

Adenosine Phosphoribosyltransferase

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48
Q

A critically important enzyme of purine salvage in rapidly dividing cells which catalyzes the deamination of adenosine to inosine.

A

Adenosine deaminase

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49
Q

Deficiency in ADA results in the disorder called

A

Severe combined immunodeficiency “SCID”

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50
Q

Can also contribute to the salvage of the bases through a reversal of the catabolism pathways. However, this pathway is less significant than those catalyzed by the phosphoribosyltransferases.

A

Purine nucleotide phosphorylases

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51
Q

The synthesis of AMP from IMP and the salvage of IMP via AMP catabolism have the net effect of deaminating _______ to _______. This process has been termed as

A

Aspartate. Fumarate. Purine nucleotide cycle.

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52
Q

This cycle is very important in muscle cells, because increases in the muscle activity create a demand for an increase in the TCA cycle, inorder to generate more ____ for the production of ___.

A

Purine nucleotide cycle. NADH. ATP.

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53
Q

However, muscle lacks most of the enzymes of the major ______ reactions. Muscle thus replenishes TCA cycle intermediates in the form of _______ generated by the purine nucleotide cycle.

A

Anaplerotic. Fumarate.

54
Q

Is the muscle-specific isoenzyme of AMP deaminase, and deficiencies in this leads to post-exercise fatigue, cramping and myalgias.

A

Myoadenylate deaminase

55
Q

Separate kinase for each nucleotide

A

Nucleoside monophosphate kinases

56
Q

Single enzyme with broad specificity

A

Nucleoside Diphosphate Kinase

57
Q

Is a condition that results from the precipitation of urate (uric acid) as monosodium urate (MSU) or ___________ crystals in the synovial fluid of the joints, leading to severe inflammation and arthritis.

A

Gout. calcium pyrophosphate dihydrate

58
Q

Most forms of gout are the result of excess _______ production or to a partial deficiency in the salvage enzyme, ______.

A

Purine. HGPRT.

59
Q

Example for gout, increased activity of PRPP synthetase leads to excess PRPP leading to increased _________ production that can increase the rate of purine degradation and subsequently increases ________ synthesis.

A

Purine nucleotide. Uric acid synthesis.

60
Q

Responsible for reforming IMP & GMP from hypoxanthine and guanine

A

HGPRT & salvage pathway

61
Q

Most forms of gout can be treated by administering this antimetabolite. This compound is a structural analog of hypoxanthine that strongly inhibits _________.

A

Allopurinol. Xanthine oxidase.

62
Q

Results from the loss of a functional HGPRT gene. The disorder is inherited as a sex-linked trait, with the HGPRT gene on the X chromosome. Patients with this defect exhibit not only symptoms of gout but also a severe malfunction of the nervous system. Patient may result to self-mutilation. Death before 20th year.

A

Lesch-Nyhan syndrome

63
Q

Most often caused by a deficiency in the enzyme adenosine deaminase. ADA deficiency selectively leads to destruction of ________, the cells that mount immune system.

A

Severe Combined Immunideficiency disease (SCID). B & T lymphocytes.

64
Q

In the absence of ADA, ______ is phosphorylated to yield levels of dATP that are 50-fold higher than normal. The levels are especially high in _______, which have abundant amounts of the salvage enzymes.

A

Deoxyadenosine. Lymphocytes.

65
Q

High concentration of dATP inhibit _________ thereby preventing other dNTPs from being produced. The net effect is to inhibit ________.

A

Ribonucleotide reductase. DNA synthesis.

66
Q

Since lymphocytes must be able to proliferate dramatically in response to antigenic challenge, the inability to synthesize DNA seriously impairs the ________, and the diseases is usually fatal unless special protective measures are taken.

A

Immune response

67
Q

A less sever immunodeficiency results when there is lack of ________, another purine degradative enzyme.

A

Purine nucleoside phosphorylase.

68
Q

A glycogen storage disease which leads to excessive uric acid production. This disorder results from a deficiency in ______ activity.

A

Von Gierke’s disease. Glucose 6 Phosphatase

69
Q

The increased availability of ____ increases the rate of flux through the PPP, yielding an elevation in the level of ____ and consequently _____ then result in excess _________.

A

G6P. R5P. PRPP. Purine biosynthesis.

70
Q

Elevated PRPP synthetase and deficiency in HGPRT & G6P

A

Gout

71
Q

HGPRT lacking

A

Lesch-Nyhan syndrome

72
Q

ADA lacking

A

SCID

73
Q

PNP lacking

A

Immunideficiency

74
Q

APRT lacking

A

Renal lithiasis

75
Q

Xanthine oxidase absent

A

Xanthinuria

76
Q

G6P deficiency

A

von Gierke disease

77
Q

Synthesis of ______ is less complex than that of purine, since the base is much simplier. The first completed base is derived from __ mole of glutamine, __ mole of ATP, __ mole of CO2 and __ mole of aspartate.

A

Pyrimidines. 1. 1. 1. 1.

78
Q

Carbamoyl phosphate used for pyrimidine nucleotide synthesis is derived from _______ & _______, within the _______. As opposed to the urea cycle CP derived from ______ & _______ in the _______.

A

Glutamine & Bicarbonate. Cytosol. Ammonia & Bicarbonate. Mitochondrion.

79
Q

The pyrimidine nucleotide precursor is synthesized by

A

Carbamoyl Phosphate Synthetase II

80
Q

Carbamoyl phosphate is the condensed with aspartate in a reaction catalyzed by the rate limiting enzyme of pyrimidine nucleotide biosynthesis known as

A

Aspartate Transcarbamoylase (ATCase)

81
Q

UMP synthesis overview: 2 ATPs needed both used in first step. One transfers _____, the other is hydrolyzed to _____. 2 condensation reactions: form _________ and ___.

A

Phosphate. ADP & Pi. Carbamoyl Aspartate & OMP.

82
Q

Pyrimidine ring is synthesized from

A

Carbamoyl phosphate and Aspartate

83
Q

Carbamoyl P for pyrimidine synthesis is formed in _____. Enzyme is ___________. And uses ________ as an N-donor.

A

Cytosol. CP II. Glutamine.

84
Q

Are attached to PRPP AFTER synthesis

A

Pyrimidines

85
Q

Diff. in Purine & Pyrimidine Biosynthesis: 3. The ring structure is assembled as a _______, not built upon PRPP. PRPP is added to the first fully formed pyrimidine base (AKA _______) forming ______ which is subsequently decarboxylated to UMP.

A

Pyrimidine base. Orotic acid. Orotate Monophosphate (OMP)

86
Q

Diff. in Purine & Pyrimidine Biosynthesis: 2. there is no branch in the pyrimidine synthesis pathway. UMP is phosphorylated twice to yield ____. (ATP is a phosphate donor). The first phosphorylation is catalyzed by ________ and then second by __________.

A

UTP. Uridylate kinase. Ubiquitous nucleoside diphosphate kinase.

87
Q

Diff. in Purine & Pyrimidine Biosynthesis: 3. UTP is aminated by the action of _________, generating CTP. The thymine nucleotides are in turn derived by _____ synthesis from dUMP or by salvage pathways from _______ or _______.

A

CTP synthase. De novo. Deoxyuridine or Deoxythymidine.

88
Q

Deoxyribonucleotide formation: purine/pyrimidine degradation are the same for ribonucleotides and deoxyribonucleotides. Biosynthetic pathways are only for ________ production. _________ are synthesized from corresponding ribonucleotides.

A

Ribonucleotide. Deoxyribonucleotide.

89
Q

DNA composed of _________. Ribose sugars in DNA lacks hydroxyl group at ______. ______ doesn’t appear in DNA (normally), ______ appears instead.

A

Deoxyribonucleotides. 2’ carbon. Uracil. Thymine (5-methyluracil)

90
Q

Formation of Deoxyribonucleotides: reduction of 2’ carbon done via a ________ catalyzed by __________.

A

Free radical mechanism. Ribonucleotide Reductases.

91
Q

Is a multifunctional enzyme that contains redox-active thiol groups for the transfer of electrons during reduction reactions. In the process of reducing _____ to _____, this becomes oxidized.

A

Ribonucleotide reductase. rNDP. dNDP.

92
Q

RR is reduced in turn by either _______ or _______. The ultimate source of the electrons is ______.

A

Thioredoxin or Glutaredoxin. NADPH.

93
Q

The electrons are shuttled through a complex series of steps involving enzymes that regenerate the reduced forms of thioredoxin and glutaredoxin. These enzymes are

A

thioredoxin reductase and glutathione reductase

94
Q

In RR: Activates the reduction CDP & UDP

A

ATP

95
Q

In RR: induces GDP reduction and inhibits reduction of CDP & UDP.

A

dTTP

96
Q

In RR: inhibits reduction of all nucleotides

A

dATP

97
Q

In RR: stimulates ADP reduction. Inhibits CDP, UDP, GDP reduction

A

dGTP

98
Q

Synthesis of Thymine Nucleotides: the de novo pathway to dTTP synthesis first requires the use of ____ from the metabolism of either ____ or ____. The dUMP is converted to dTMP by the action of _______.

A

dUMP. UDP or CDP. Thymidylate synthase.

99
Q

Synthesis of dTMP from dUMP: 1. the methyl group (thymine is 5-methyl uracil) is donated by _________, similarly to the donation of methyl groups during the biosynthesis of purines.

A

N5,N10-methylene tetrahydrofolate

100
Q

Synthesis of dTMP from dUMP: 2. the unique property of the action __________ is that the THF is converted to _________. The only such reaction yielding DHF & THF.

A

Thymidylate synthase. Dihydrofolate.

101
Q

Synthesis of dTMP from dUMP: 3. in order for the thymidylate synthesis to continue, THF must be degenerated from DHF. This is accomplished through the action of ___________.

A

Dihydrofolate reductase (DHFR)

102
Q

Synthesis of dTMP from dUMP: 4. THF is them converted to N5, N10-THF via the action of __________.

A

Serine hydroxymethyl transferase

103
Q

Synthesis of dTMP from dUMP: 5. The crucial role of ____ in thymidine nucleotide biosynthesis makes it an ideal target for chemotherapeutic agents such ______ & ______, which are structural analogues of _____ & ______.

A

DHFR. Sulfonamides & Trimethoprim. PABA & Folic acid.

104
Q

Sulfonamide susceptible organisms, unlike mammals, cannot use exogenous folate but must synthesize it from _______. This pathways is thus essential for production of ______ & ______ synthesis in bacteria.

A

PABA. Purine & Nucleic acid.

105
Q

Mammalian cells lack the enzymes required for folate synthesis from PABA and depend on exogenous sources of folate; therefore they are not susceptible to _______.

A

Sulfonamides

106
Q

Is also useful as an antibacterial; it does not affect mammalian cells because 50k less efficient in inhibition of mammalian ________.

A

Trimethoprim. Dihydrofolate reductase.

107
Q

This is another DHFR inhibitor which is used in cancer chemotherapy.

A

Methotrexate

108
Q

The salvage pathway to dTTP synthesis involves this enzyme which can use either thymidine or deoxyuridine as substrate. Thymidine+ATPTMP+ADP. Deoxyuridine+ATPdUMP+ADP.

A

Thymidine kinase

109
Q

The activity of this is unique in that it fluctuates with the cell cycle, rising to peak activity during the phase of DNA synthesis; it is inhibited by ____.

A

Thymidine kinase. dTTP.

110
Q

The regulation of pyrimidine synthesis occurs mainly at the first step which is catalyzed by

A

Aspartate transcarbamoylase, ATCase

111
Q

ATCase is inhibited by

A

dUTP, UDP, CTP & UTP “DUCU”

112
Q

ATCase is activated by

A

ATP

113
Q

Is a multifunctional protein in mammalian cells. It is capable of catalyzing the formation of carbamoyl phosphate, carbamoyl aspartate, and dihydroorotate.

A

ATCase

114
Q

ATCase, and therefore the activity of CPS II, is localized to the _______ and prefers _______ as a substrate.

A

Cytoplasm. Glutamine.

115
Q

The role of ______ in ATCase regulation is to act as a comoetitive inhibitor of the glutamine binding site.

A

Glycine

116
Q

As in the regulation of purine synthesis, ___ levels also regulate pyrimidine biosynthesis at the level of PRPP formation. An increase in the level of _____ results in an activation of pyrimidine synthesis.

A

ATP. PRPP.

117
Q

This enzyme is competitively inhibited by UMP and to a lesser degree by CMP.

A

OMP decarboxylase

118
Q

Is feedback inhibited by CTP and activated by GTP

A

CTP synthase

119
Q

Catabolism of the pyrimidine nucleotides leads ultimately to ______ or ______ and NH3 & CO2.

A

B-alanine. B-aminoisobutyrate.

120
Q

Serve as a NH2 donors in transamination of a-ketoglutarate to glutamate. A subsequent reaction converts the products to ______ or ________.

A

B-alanine & B-aminoisobutyrate. Malonyl CoA. Methylmalonyl CoA.

121
Q

The salvage of pyrimidine bases has less significance than that of the _____, owing to the solubility of the by products of pyrimidine catabolism.

A

Purines

122
Q

Uracil can be salvaged to form UMP through the concerted action of

A

Uridine phosphorylase & Uridine kinase

123
Q

Formed when CMP and UDP are degraded

A

B-alanine

124
Q

Formed when dTMP is degraded

A

B-aminoisobutyrate

125
Q

Can be diverted to fatty acid synthesis

A

Malonyl CoA

126
Q

Converted to succinyl CoA and can be shunted to TCA cycle

A

Methylmalonyl CoA

127
Q

Formation of dTMP, by salvage of thymine requires

A

Thymine phosphorylase and Thymine kinase

128
Q

The salvage of deoxycytidine is catalyzed by

A

Deoxycytidine kinase

129
Q

Two inherited disorders affecting pyrimidine biosynthesis are the result of deficiencies in the bifunctional enzyme catalyzing the last two steps of UMP synthesis

A

Orotate phosphoribosyl transferase & OMP decarboxylase

130
Q

Deficiency in pyrimidine catabolism result in this that causes retarded growth and severe anemia caused by hypochromic erythrocytes and megaloblastic bone marrow. _______ is also common with this.

A

Orotic aciduria. Leukopenia.

131
Q

Orotic aciduria can be treated with these which leads to increased UMP production via the action of _________.

A

Uridine/Cytidine. Nucleoside kinase.

132
Q

Inhibits CPS II thus attenuating orotic acid production.

A

UMP

133
Q

Can also cause orotic aciduria because it can act as an alternative substrate and compete with orotic acid for degradation.

A

Allopurinol

Biochemistry (20 decks)

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