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Hematology Block 1 > Biochemistry > Flashcards

Biochemistry Flashcards

1
Q

Common features of Purine and Pyrimidine Nucleotide synthesis:

A

–Nucleotides are synthesized from smaller molecules

–Ribose 5-phosphate from the pentose phosphate pathway is utilized

–Base rings are built from smaller components (e.g. amino acids, CO2)

–Single purines or pyrimidines are built first and other nucleotides are derived from these

–1-carbon carrier tetrahydrofolate is required

–Process is highly regulated to ensure organismal cellular requirements are met and generate the correct amounts of each nucleotide

–Loss of normal regulation can result in disease

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2
Q

Why is tetrahydrofolate important for purine and pyrimidine synthesis?

A

THF is a 1-carbon carrier, which adds a carbon to the 2 and 8 position of purines

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3
Q

ribose-5-phosphate is the precursor to _____, an activated form of ribose that initiates synthesis

A

PRPP

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4
Q

_____ is the common precursor to purine nucleotides and the branch point for the synthesis of different purines.

A

IMP

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5
Q

Where does ribose-5-phosphate come from? Why is it important to nucleotide biosynthesis?

A

Ribose-5-P is derived from glucose, primarily from the Pentose Phosphate Pathway or via phosphorolysis of nucleosides (salvage pathway). It is the starting point of purine biosynthesis along with ATP.

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6
Q

______ is the precursor to PRPP

A

Ribose-5-Phosphate

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7
Q

What is PRPP?

A

5-phosphoribosyl-1-pyrophosphate

Pentose molecule that participates in synthesis and salvage of purines and pyrimidines

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8
Q

Ribose-5-P + ATP –> PRPP is catalyzed by WHAT enzyme?

A

PRPP synthetase

This is an important enzyme for regulation of PRPP synthesis, but is technically NOT the committed step.

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9
Q

Arts syndrome is a(n) ____ disorder in ______

A

X-linked genetic disorder in PRPP synthetase enzyme (responsible for catalyzing ribose-5-P –> PRPP).

Presents with severe nervous system abnormalities

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10
Q

What controls the production of PRPP?

A
  • Amount of ribose-5-phosphate controls the rate of formation
  • Pi activates PRPP synthetase (high Pi indicates low nucleotide levels)
  • Purine nucleotides inhibit PRPP synthetase
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11
Q

Increases in PRPP synthetase lead to WHAT?

A

Increased levels of purines and gout

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12
Q

What are the consequences of reduced PRPP synthetase activity?

A

Reduced purine levels; hypoxanthine is absent from urine and uric acid is reduced in serum

e.g. Arts Syndrome

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13
Q

Glutamine + PRPP –> _____?

A

5-phosphoribosylamine

(Glutamine contributes the first NH2)

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14
Q

What is the committed step of purine biosynthesis?

A

Glutamine + PRPP –> 5-phosphoribosylamine (catalyzed by glutamine phosphoribosyl amidotransferase)

This reaction is irreversible

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15
Q

How is the committed step of purine biosynthesis regulated?

A

The step is glutamine + PRPP –> 5-phosphoribosylamine (catalyzed by glutamine phosphoribosyl amidotransferase)

Reaction is inhibited by AMP, GMP, IMP, and XMP

Reaction/enzyme is stimulated by PRPP

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16
Q

The monomer form of glutamine phosphoribosyl amidotransferase is _____ and the dimer form is _____

A

monomer form is ACTIVE

dimer form is INACTIVE

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17
Q

High ____ shifts the enzyme glutamine phosphoribosyl amidotransferase to the more active _____ form

A

High PRPP

more active MONOMERIC form

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18
Q

___ levels vary greatly in the cell and play a key role in regulating purine synthesis. Why?

A

PRPP levels.

PRPP levels are usually well below the Km for PRPP

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19
Q

glutamine phosphoribosyl amidotransferase is regulated via ____ kinetics with glutamine and _____ kinetics with PRPP. Which influences the enzyme rate more?

A

Glutamine - hyperbolic kinetics

PRPP - sigmoidal kinetics

Glutamine levels are near Km and don’t vary much - doesn’t influence rate significantly.

PRPP levels vary widely and can be much lower than Km, so this plays an important role in enzyme activity

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20
Q

Describe the regulation of glutamine phosphoribosyl amidotransferase by AMP, GMP, and IMP

A

There are two distinct regulatory binding sites on this enzyme.

AMP has its own site

GMP, IMP, and XMP have a separate site.

One alone inhibits the reaction somewhat. Presence of AMP + GMP/IMP causes even more inhibition.

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21
Q

IMP is the common precursor of ____ nucleotides

A

purine

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22
Q

_____ is a carbon donor at 2 steps of IMP (purine) synthesis

A

N-formyl-tetrahydrofolate

(derived from folate)

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23
Q

Sulfa antibiotics inhibit bacterial ____ synthesis

A

folic acid

(which inhibits nucleic acid synthesis)

Because humans don’t synthesize folic acid but acquire it by the diet, these drugs don’t interfere with human purine synthesis and DNA replication

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24
Q

How is Methotrexate used to treat cancer?

A

•Methotrexate is an anti-tumor drug that reduces synthesis of tetrahydrofolic acid compounds, including N10-formyl-tetrahydrofolate by inhibiting DHFR

–Reduces purine synthesis, which slows down DNA replication

–Slows tumor cell growth, but also affects normally dividing cells leading to adverse side effects

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25
IMP is a precursor for both ___ and \_\_\_
AMP and GMP
26
\_\_\_\_ is the base of IMP
Hypoxanthine
27
AMP synthesis requires ___ for energy, along with \_\_\_
Requires GTP for energy Aspartate --\> releases fumarate
28
GMP synthesis uses ___ for energy, along with WHAT
ATP for energy along with NAD and glutamine
29
If ATP is high then GMP/GTP is \_\_\_\_\_\_
Increased
30
If GTP is high then AMP/ATP is \_\_\_\_\_
increased
31
\_\_\_\_\_ competitively inhibits IMP dehydrogenase
GMP
32
\_\_\_\_ competitively inhibits adenylosuccinate synthetase
AMP
33
Mycophenolic acid (Ribavirin) inhibits _____ and \_\_\_\_\_
IMP dehydrogenase and GMP formation
34
IMP dehydrogenase is inhibited by _____ and \_\_\_\_\_. Why is this useful?
Inhibited by Ribavirin and Mycophenolic acid Employed as an immunosuppressant to reduce lymphocyte proliferation and prevention of graft rejection
35
\_\_\_\_\_\_ converts AMP to ADP
Adenylate kinase (AMP kinase) Requires ATP
36
\_\_\_\_\_\_ converts GMP to GDP
guanylate kinase (GMP kinase) Requires ATP
37
\_\_\_\_\_ converts ADP, GDP, and other NDPs to triphosphates
Nucleoside diphosphate kinase (enzyme has broad specificity) Requires ATP
38
The purine ring is built on \_\_\_\_
5-phosphoribosyl 1-amine
39
Nucleic acid is digested in the stomach by \_\_\_\_
pepsin
40
\_\_\_\_ and ____ secreted by the pancreas digest RNA and DNA --\> oligonucleotides
RNAses and DNAses --\> oligonucleotides
41
\_\_\_\_\_ degrades oligonucleotides --\> NMPs and dNMPs
phosphodiesterases
42
\_\_\_\_ removes the phosphate groups (during purine degradation) --\> nucleosides
Nucleotidases (or phosphatases)
43
\_\_\_\_ degrades nucleosides --\> free bases plus ribose and deoxyribose
Nucleosidases (nucleosidases generate pyrimidines and purines)
44
Some purines are converted to \_\_\_\_, which enters the bloodstream and is mainly excreted in the urine
uric acid
45
non-primate mammals have an enzyme _____ that converts uric acid to allantoin (5-10x more soluble compared to uric acid)
urate oxidase
46
Rasburicase:
Recombinant urate oxidase - used in humans to reduce uric acid levels in people that are hyperuricemic
47
\_\_\_\_ nucleotide degradation products are all soluble, whereas ____ nucleotide degradation products can become insoluble
Pyrimidine products are SOLUBLE Purine products can be INSOLUBLE
48
Hyperuricemia can arise due to ___ and \_\_\_\_, resulting in \_\_\_\_
Hyperuricemia can arise due to **overproduction** of uric acid and **limited excretion**, resulting in **gout**
49
Describe the degradation of AMP to uric acid
AMP --\> IMP --\> inosine OR AMP --\> adenosine --\> inosine THEN inosine --\> hypoxanthine hypoxanthine --\> xanthine (xanthine oxidase) xanthine --\> uric acid
50
Describe the degradation of GMP to uric acid
GMP --\> guanosine guanosine --\> guanine guanine --\> xanthine xanthine --\> uric acid (xanthine oxidase)
51
Uric acid is generated in the \_\_\_\_, transported to the \_\_\_\_, and excreted in \_\_\_\_
Uric acid is generated in the LIVER, transported to the KIDNEY, and excreted in URINE
52
\_\_\_\_\_ inhibits xanthine oxidase and reduces uric acid levels (Gout therapeutic)
Allopurinol
53
Describe the two paths of AMP --\> inosine
1. AMP loses amino group --\> IMP (AMP deaminase) --\> inosine (5'-nucleotidase) 2. AMP --\> adenosine (5'-nucleotidase) --\> inosine (adenosine deaminase)
54
Blockage of adenosine deaminase results in \_\_\_\_\_
SCID ## Footnote Even though there is another pathway to yield inosine, the adenosine deaminase enzyme is involved in formation of 2-deoxyadenosine, yielding an excess of dATP which is toxic and leads to cell death.
55
In humans, ___ have highest levels of adenosine deaminase (ADA)
lymphocytes
56
Adenosine deaminase (ADA) catalyzes:
Adenosine --\> inosine Deoxyadenosine --\> deoxyinosine
57
Genetic deficiency of ADA results in an accumulation of \_\_\_
dAMP --\> dATP
58
High levels of dATP inhibits \_\_\_\_\_\_, resulting in a reduction in DNA synthesis
ribonucleotide reductase
59
Why are lymphocytes affected by adenosine deaminase deficiency?
Lymphocytes have the highest levels of adenosine deaminase. Deficiency results in accumulation of dATP, which inihibits ribonucleotide reductase, reducing DNA synthesis. dATP levels are toxic. Lymphocytes die, resulting in low lymphocyte counts, and inability to combat infection --\> SCID
60
What is the importance of AMP deaminase and what happens when deficienct?
AMP deaminase catalyzes AMP --\> IMP. Selective only for AMP. Functions in skeletal muscle. AMP deaminase deficiency results in skeletal muscle myopathy and exercise induced fatigue and cramps. Often asymptomatic, because only affects ribonucleotide pathway (AMP --\> IMP) so you don't get an accumulation of dATP.
61
Some cell types, e.g. ____ use salvage as the major source for nucleotides
lymphocytes
62
Explain how nucleotides can be salvaged from nucleosides
Phosphorylation by kinases (adenosine kinase)
63
Bases can be salvaged to nucleotides how?
Addition of phosphoribose using PRPP by phosphoribosyl transferases (APRT)
64
IMP and GMP use what enzyme to promote purine salvage?
hypoxanthine-guanine phosphoribosyltransferase (HGPRT)
65
AMP uses what enzyme to promote purine salvage?
adenine phosphoribosyltransferase (APRT)
66
HGPRT can convert purine analogs into \_\_\_\_\_
anti-tumor compounds
67
Why are purine salvage reactions irreversible?
Due to PPi cleavage by pyrophosphatase (Requires PPRT, which is converted to PPi - can't revert back)
68
Deficiency of purine nucleoside phosphorylase:
Nucleosides accumulate, resulting in an increase in dGTP and decrease in GMP which may contribute to symptoms. T cell immunodeficiency
69
What process does purine nucleoside phosphorylase catalyze?
purine nucleoside --\> purine + ribose-1-P (inosine --\> hypoxanthine; guanosine --\> guanine) Basically, the process of converting a nucleoside to a purine base.
70
PRPP + base --\> nucleotide + PPi is catalyzed by WHAT
APRT and HGPRT phosphoribosyltransferases
71
Most cases of hyperuricemia (gout) is caused by what?
underexcretion of uric acid A small amount of cases are due to overproduction of uric acid
72
By what mechanism is uric acid overproduced?
Loss of regulation at the committed step of purine nucleotide synthesis. Mutations in PRPP synthetase result in high levels of PRPP and overproduction of purines. Lesch-Nyhan Syndrome Chemotherapy
73
What causes Lesch-Nyhan syndrome?
X-linked recessive disorder with a deficiency of HGPRT Cannot salvage hypoxanthine or guanine ➞ bases degraded to uric acid ➞ increased uric acid Decreased salvage of hypoxanthine and guanine results in increased levels of PRPP and reduced AMP and GMP Excess uric acid causes gout
74
How does chemo cause hyperuricemia?
High cell death results in excess purine degradation products
75
Factors that increase PRPP synthetase activity lead to:
–Increased levels of PRPP –Increases in the activity of glutamine phosphoribosyl amidotransferase (rate limiting step) –Increases in the production of 5-phosophylribosyl 1-amine and nucleotides
76
von Gierke disease is characterized by what?
genetic deficiency of glucose-6-phosphatase
77
Reduced glucose 6-phosphatase results in more glucose 6-phosphate shunted into the _______ pathway, since pathway to glucose production is blocked. This generates more \_\_\_\_\_, ultimately resulting in WHAT?
Shunted into the pentose phosphate pathway Generates more ribose 5-phosphate ➞ PRPP ➞ stimulates glutamine phosphoribosyl amidotransferase activity ➞ more nucleotide synthesis
78
What are current treatments for gout?
Acute gout: anti-inflammatory agents, colchicine (treats symptoms but no effect on high uric acid levels) Chronic gout: –Inhibit uric acid production * Allopurinol and febuxostat inhibit xanthine oxidase - lower purine and uric acid levels * Pegloticase and rasburicase convert uric acid to more soluble allantoin –Promotes renal excretion of uric acid: probenecid, lesinurad
79
Allopurinol inhibits what?
uric acid synthesis
80
Describe how allopurinol inhibits uric acid synthesis:
–Structural analog of hypoxanthine –Allopurinol converts to oxypurinol, which is an irreversible inhibitor of xanthine oxidase –Accumulates xanthine and hypoxanthine, which are more soluble than uric acid –Hypoxanthine can be salvaged, which reduces levels of PRPP and de novo purine synthesis
81
What is Febuxostat?
Inhibitor of xanthine oxidase (ultimately inhibits production of uric acid)
82
Describe the relationship between tumor lysis syndrome and hyperuricemia:
* Cancer patients with large tumors and undergoing treatment have high levels of serum and urine uric acid * Results from the destruction of tumor cells and nucleic acid degradation due to radiation therapy and administration of cytotoxic drugs * Can treat patients undergoing cancer therapy with allopurinol or rasburicase to reduce uric acid levels
83
What amino acids are required to develop the pyrimidine ring?
Gln and Asp (with CO2)
84
Describe the first step of pyrimidine synthesis:
•Glutamine + CO2 ➞ carbamoyl phosphate –Glutamine provides N –Enzyme is carbamoyl phosphate synthetase II (CPS-II) •Committed step –CPS-II is inhibited by UTP and activated by PRPP
85
What 3 activities are catalyzed by CAD enzyme?
First 3 activities of the pyrimidine synthesis pathway all reside within the same multisubunit protein - **CAD** (**C**arbamoyl phosphate synthetase II, **A**spartate transcarbamoylase, **D**ihydroorotase) •Dihydroorotate ➞ orotate catalyzed by dihydroorotate dehydrogenase This enzyme functions to close the pyrimidine ring and create orotic acid
86
orotic acid --\> ___ --\> \_\_\_\_ What enzymes catalyze this?
orotic acid --\> OMP --\> UMP Two enzymes are subunits of multisubunit *UMP synthase* (*Orotate phosphoribosyl-transferase, Orotidine 5’-P decarboxylase*)
87
Hereditary Orotic Aciduria
–Mutations in UMP Synthase (either subunit) result in poor growth, anemia, and high levels of orotic acid in urine due to lack of pyrimidines –Treat with the addition of uridine –Uridine ➞➞ UTP (salvage pathway) * UTP ➞ CTP (replenishes pools of UTP and CTP) * UTP inhibits CSPII ➞ reduces de novo synthesis of orotic acid to normal levels
88
How is CTP synthesized from UTP?
•UMP is phosphorylated ➞ UDP ➞ UTP –UMP Kinase UMP + ATP ➞ UDP + ADP –NDP kinase UDP + ATP ➞ UTP + ADP •CTP is produced from UTP –CTP synthetase + glutamine (provides the N) (CTP is a negative feedback regulator)
89
In humans, the key regulated step of pyrimidine synthesis is the ____ step
committed step (CPS II) * PRPP activates CPS II (allosteric activator) * ATP is required for 1st step (helps balance purine/pyrimidine ratio) * UTP and UDP are feedback inhibitors of CPS II
90
How are pyrimidines degraded?
•Unlike the purine ring, the pyrimidine rings are degraded to highly soluble products –Cytosine ➞ uracil ➞ b-alanine –Thymine ➞ b-aminoisobutyrate * b-alanine and b-aminoisobutyrate are excreted in urine or converted to malonyl-CoA and methylmalonyl-CoA ➞ fatty acid biosynthesis * High solubility of pyrimidine derivatives renders them less significant clinically compared to purines
91
How are pyrimidines salvaged?
Pyrimidine bases can be salvaged to nucleosides ➞ nucleotides Uracil + ribose 1-phosphate ➞ uridine (*nucleoside phosphorylase*) Uridine + ATP ➞ UMP (other pyrimidines similar) (*nucleoside kinases*)
92
Deoxyribonucleotides are derived from \_\_\_\_\_\_
ribonucleoside diphosphates
93
Describe the process of how Deoxyribonucleotides are derived:
Deoxyribonucleotides are derived from ribonucleoside diphosphates Need to reduce ribose to deoxyribose (2’-OH ➞ H) - Enzyme: *Ribonucleotide reductase* Requires *thioredoxin* as cofactor to supply H NADPH from pentose phosphate pathway provides H to replenish *thioredoxin*
94
Hydroxyurea is an _____ compound that inhibits \_\_\_\_\_\_\_
anti-tumor coumpound that inhibits *ribonucleotide reductase* (degrades R2 tyrosyl free radical) This reduces dNDPs (and dNTPs), thus reducing DNA synthesis
95
Describe the process of reduction and hydrolysis of dUTP to dUMP:
* UMP is phosphorylated to form UDP and UTP * UDP is a substrate for ribonucleotide reductase (RR) and forms dUDP then ➞ dUTP. However, don’t use dUTP in DNA synthesis so dUTP is quickly hydrolyzed to dUMP. Reduces likelihood that dUTP will be erroneously incorporated into DNA * Alternative path to dUMP via deamination of dCMP. dCMP deaminase - regulated by dCTP (+) and TTP (-): maintains balance between dCTP and TTP
96
Describe the synthesis of TMP from dUMP
dUMP --\> dTMP --\> dTTP dUMP --\> dTMP (enzyme *thymidylate synthase*) + N5,N10-methylene tetrahydrofolate. N5,N10-methylene tetrahydrofolate is derived from dihydrofolate. Need regeneration of dihydrofolate by NADPH for continual DNA replication. Only cellular reaction in which FH4 is oxidized to FH2. dTMP ➞ dTTP by successive kinase phosphorylations
97
Describe the modes of regulation of *ribonucleotide reductase* activity
Enzyme levels are controlled by transcriptional and post-transcriptional mechanisms. Reaction is activated by ATP and inhibited by dATP. (Regulation helps balance relative amounts of NTPs and dNTPs) Cross-regulation by dNTPs (Helps balance correct amounts of each dNTP)
98
Ribonucleotide reductase has 2 allosteric sites: one controls _____ and the other controls \_\_\_\_\_\_
_Activity_ (ATP activates the enzyme and dATP inhibits activity. Maintains proper balance of ribo and deoxyribonucleotides) _Substrate specificity sites_ (Complex binding of one type of dNTP cross-regulates levels of other dNDPs. Maintains proper balance of each deoxyribonucleotide) –Example: dATP (purine) binding to allosteric site enhances reduction of pyrimidine NDPs (UDP, CDP) to dNDPs (TDP, dCDP)
99
5-flurouracil:
Anti-tumor drug that is designed to slow DNA synthesis and tumor growth 5-Fluorouracil (uracil analog) is converted to 5-fluorodeoxyuridine monophosphate, which permanently binds thymidylate synthase. This inactivates the enzyme and reduces conversion of dUMP ➞ dTMP.
100
Methotrexate:
Dihydrofolate reductase + NADPH ➞ reduces dihydrofolate (FH2) ➞ tetrahydrofolate (FH4) Methotrexate is a competitive inhibitor of dihydrofolate reductase and reduces levels of tetrahydrofolate and N5,N10-methylene tetrahydrofolate and reduces conversion of dUMP ➞ dTMP
101
6-Mercaptopurine:
6-mercaptopurine (6-MP; guanine analog) - competes with guanine and hypoxanthine and is converted to 6-MMP (6-mercaptopurine monophosphate) by HGPRT + PRPP Negatively regulates PRPP amidotransferase - reduced nucleotides (Inhibits IMP ➞ AMP and IMP ➞ GMP pathways) 6-MP also converted to additional active compounds
102
Leflunomide:
Anti-tumor drug Inhibits dihydroorotate dehydrogenase Blocks orotate and pyrimidine production

Hematology Block 1 (5 decks)

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