Module 7 Flashcards
Monomeric units that make the nucleic acids DNA and RNA
Nucleotides
Responsible for the storage and passage of theinformation needed for the productions of proteins?
Nucleic acids
Each nucleotides consists of?
Pentose sugar,
Nitrogenous base
Phosphate group
Nucleotides result from linking one or more phosphates with a nucleoside onto the 5’ end of the molecule through
Esterfication
5-carbon sugar in a pentose ring form
Pentose sugar
RNA contains ribose, which has a hydroxyl group in both the
2 and 3 position
DNA has only a single hydroxyl group in the
3 position
Lacks a 2’-OH group
2 deoxyribose
Bond between adenine and deoxyribose
Glycosidic bond
Nucleosides
dAdenosine
Nucleotides
dAdenylic acid ( dAMP)
A nitrogenous base is attached by a glycosidic bond to the __________of the nucleotide’s sugar
1 carbon
Purinesconsist of linked 5-membered and 6membered rings__________ and _________) which can be found in DNA or RNA
Adenine A
Guanine G
5 and 6 membered rings
Pyrimidines consist of 6-membered rings
Cytosine C
Thymine T
Uracil U
Found in DNA and RNA
Cytosine
Found in DNA
Thymine
Found in RNA
Uracil
Nitrogenous base are
Planar, aromatic, and heterocyclic
Nitrogenous base derived from
Purine and pyrimidines
Nitrogenous base numbering of bases are
Unprimed
The sugar is linked to the base via a ___________ bond to the __________________
b-Nglycosidic bond
N-1 of pyrimidines
N-9 of purines
Purine nucleosides end in
Sine
Pyrimidine nucleosides end in
Dine
Nucleotides are linked together by ________________ between the _________ on the sugar of one nucleotide through a phosphate molecule to the ____________ on the sugar of another nucleotide
Phosphodiesterase bonds
3 hydroxyl
5 hydoxyl
Bondsof nucleotides are broken by?
Phosphodiesterase
Bond between complementary nucleotide chain and normal nucleotide chain.
Hydrogen bond
a second messenger in response to nitric oxide during smooth muscle relaxation
cAMPand cGMP
Function of nucleodtides
Syhtesis of cyclic AMP and GMP
Methyl group transfer
Glycogen, bilirubin, phosphoglyceride synthesis
Nucleotides absorb
UV lights
used as antivirals and in cancer chemotherapy
Synthetic nucleotide
targets for cancer chemotherapy and viral disease treatment
Purine and pyrimidine synthesis
activated precursors in nucleic acid synthesis
Nucleoside triphosphate
purines are not initially synthesized as free bases–First purine derivative formed is
Inosine monophophate
AMP and GMP are formed from
IMP or inosine monophosphate
The activated sugar used is 5-phosphoribosyl-1pyrophosphate, PRPP
Inosine monophosphate
PRPP is generated by the action of PRPP synthetase and requires energy in the form of
ATP
IMP is inhibited by
ADP and GDP (Allosteric
First committed step of purine synthesis
IMP
The major site of purine synthesis is in the
Liver
Synthesis of the purine nucleotides begins with ____________ and leads to the first fully formed nucleotide, ________________
PRPP
Inosine 5 moniphosphate
Synthesis of IMP requires
5ATP 2glutamine 1glycine 1Co2 1aspartate 2formate
The pathway leading to AMP requires energy in the form of
GTP
leading to GMP requires energy in the form of
ATP
Important enzyme and product in synthesis of AMP
Adenylosucinate lyase
Fumarate
Important enzyme and product in synthesis of GMP
GMP syhthetase
Glutamine and glutamate
The utilization of GTP in the pathway to AMP synthesis allows the cell to control the proportions of AMP and GMP to near ____________
Equivalence
Increase GTP
increase AMP
The synthesis of PRPP by PRPP synthetase is feed-back inhibited by
Purine 5 nucleotides
The essential rate limiting steps in purine biosynthesis occur at the
First two step of the pathway
PRPP synthetase
Amino transferase reaction
The amidotransferase reaction (2ndstep) catalyzed by PRPP glutamyl amidotransferase is also feed-back inhibited allosterically by
binding ATP, ADP and AMP at one inhibitory site and GTP, GDP and GMP at another
Increase ATP
Increase GMP
Increase AMP
Increase GMP
Increase GMP
Increase AMP
GTP AMP
Adenylosuccinate
ATP GMP
Xanthylic acid
Catabolism of the purine nucleotides leads ultimately to the production of ___________ which is insoluble and is excreted in the urine as __________
Uric acid
Sodium urate crystals
The synthesis of nucleotides from the purine bases and purine nucleosides takes place in a series of steps known as the
Salvage pathway
The free purine bases, adenine, guanine, and hypoxanthine, can be reconverted to their corresponding nucleotides by
Phosphoribosylation
Two key transferase enzymes are involved in the salvage of purines
Adenosine phophoriboyltransferase
hypoxanthine-guanine phosphoribosyltransferase
A critically important enzyme of purine salvage in rapidly dividing cells is ___________ (ADA) which catalyzes the deamination of adenosine to inosine
Adenosine deaminase
Deficiency in ADA results in the disorder called
Severe combined immunodeficiency
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
Purine nucleotide phosphorylases
The synthesis of AMP from IMP and the salvage of IMP via AMP catabolism have the net effect of deaminating aspartate to
Fumarate
Catabolism of purine nucleotide
purine nucleotide cycle
the muscle-specific isoenzyme of AMP deaminase, and deficiencies in myoadenylate deaminase lead to post-exercise fatigue, cramping and myalgias
Myoadenylate deaminase
Clinical problems associated with nucleotide metabolism in humans are predominantly the result of
Abnormal catabolism of purine
Most forms of gout are the result of _______________ or to a partial deficiency in the salvage enzyme, __________
Excess purine production
HGPRT
Responsible for re-forming IMP and GMP from hypoxanthine and guanine
HGPRT and the salvage system
Most forms of gout can be treated by administering the antimetabolite
Allopurinol
Allopurinol structural analog of hypoxanthine that strongly inhibits
Xanthine oxidase
condition that results from the precipitation of urate (uric acid) as monosodium urate (MSU) or calcium pyrophosphate dihydrate (CPPD) crystals in the synovial fluid of the joints, leading to severe inflammation and arthritis
Gout
syndrome results from the loss of a functional HGPRT gene
Lesch nyhan syndrome
The disorder is inherited as a sex-linked trait, with the HGPRT gene on the
X chromosome q 26-27
Patients with this defect exhibit not only severe symptoms of gout but also a severe malfunction of the nervous system. •In the most serious cases, patients resort to selfmutilation. •Death usually occurs before patients reach their
20th year
most often (90%) caused by a deficiency in the enzyme adenosine deaminase (ADA
SCID
ADA deficiency selectively leads to a destruction of ________________, the cells that mount immune responses
B and T lymphocytes
In the absence of ADA, ______________ is phosphorylated to yield levels of dATP that are 50-fold higher than normal
Deoxyadenosine
The net effect of SCID is to inhibit __________ synthesis
DNA
Since lymphocytes must be able to proliferate dramatically in response to antigenic challenge, the inability to synthesize DNA seriously impairs the immune responses, and the disease is usually fatal in infancy unless special protective measures are taken
Nice to know
A less severe immunodeficiency results when there is a lack of __________________ another purinedegradative enzyme
Purine nucleoside phophorylase PNP
Glycogen storage disease that also lead to excessive uric acid production
Von gierke disease
Von gierke results from a dificiency in
Glucose 6 phosphatase
The increased availability of glucose-6phosphate increases the rate of flux through the pentose phosphate pathway, yielding an elevation in the level of ribose-5-phosphate and consequently PRPP
Nice to know
Pyrimidine Nucleotide Biosynthesis
1 glutamine
1 ATP
1 CO2
1 aspartate
carbamoyl phosphate used for pyrimidine nucleotide synthesis is derived from
Glutamine and bicarbonate within the cytosol
urea cycle carbamoyl phosphate derived from
Ammonia and bicarbonate within the mitochondrion
Urea cycle: pyrimidine
CPS 1; CPS 2
Carbamoyl phosphate is then condensed with aspartate in a reaction catalyzed by the rate limiting enzyme of pyrimidine nucleotide biosynthesis
Aspartate transcarbamoylase
UMP Synthesis Overview •2 ATPs needed: both used in first step
Transfer phosphate
Hydrolyzed ADP and Pi
UMP syhtesis 2 condensation reactions
Carbamoyl aspartate
OMP
Pyrimidine ring syhtesize from
Carbomyl phosphate and aspartate
Purine/Pyrimidine degradation are the same for ribonucleotides and deoxyribonucleotides •Biosynthetic pathways are only for ribonucleotide production •Deoxyribonucleotides are synthesized from corresponding ribonucleotides
Nice to know
Ribose sugar in DNA lacks hydroxyl group at
2 carbon
Reduction of 2’ carbon done via a free radical mechanism catalyzed by
Ribonucleotide reductase
a multifunctional enzyme that contains redox-active thiol groups for the transfer of electrons during the reduction reactions
Ribonucleotide reductase
RR is reduced in turn, by either
Thioredoxin or glutaredoxin
The ultimate source of the electrons is
NADPH
ATP ACTIVATES REDUCTION OF
CDP and UDP
INHIBITS REDUCTION OF ALL NUCLEOTIDES
dATP
STIMULATES ADP REDUCTION •INHIBITS CDP,UDP,GDP REDUCTION
dGTP
INDUCES GDP REDUCTION •INHIBITS REDUCTION OF CDP. UDP
dTTP
The dUMP is converted to dTMP by the action of
Thymidylate synthase
The de novopathway to dTTP synthesis first requires the use of dUMP from the metabolism of either UDP or CDP
Nice to know
The methyl group (recall that thymine is 5-methyl uracil) is donated by
N5 N10 methylene
The unique property of the action of thymidylate synthase is that the THF is converted to _________________, the only such reaction yielding DHF from THF
Dihydrofolate
In order for the thymidylate synthase reaction to continue, THF must be regenerated from DHF. This is accomplished through the action of
Dihydrofolate reductase
THF is then converted to N5,N10-THF via the action of _________________
Serine hydroxymethyl transferase
The crucial role of DHFR in thymidine nucleotide biosynthesis makes it an ideal target for chemotherapeutic agents such as ___________ and ____________, which are structural analogues of PABA and Folic acid
Sulfonamides
Trimethoprim
cannot use exogenous folate but must synthesize it from PABA
Sulfonamide susceptible organisma
also useful as an antibacterial; it does not affect mammalian cells because it is about 50,000 times less efficient in inhibition of mammalian dihydrofolate reductase
Trimethoprim
used in cancer chemotherapy
Methotrexate
The salvage pathway to dTTP synthesis involves the enzyme ___________ which can use either thymidine or deoxyuridine as substrate
Thymidine kinase
Thymidine kinase is inhibited by
dTTP
The regulation of pyrimidine synthesis occurs mainly at the first step which is ctalyzed by
Aspartate trabscarbamoylase, ATCase
ATCase is inhibited by
CTP, UDP, UTP, and dUTP
multifunctional protein in mammalian cells. It is capable of catalyzing the formation of carbamoyl phosphate, carbamoyl aspartate, and dihydroorotate
ATCase
ATCase, and therefore the activity of CPSII, is localized to the __________ and prefers ___________ as a substrate
Cytoplasm
Glutamine
The role of glycine in ATCase regulation is to act as a competitive inhibitor of the glutamine binding site
Glutamine binding site
As in the regulation of purine synthesis, ATP levels also regulate pyrimidine biosynthesis at the level of
PRPP formation
Catabolism of the pyrimidine nucleotides leads ultimately to __________(when CMP and UMP are degraded
Beta alanine
when dTMP is degraded catabolism of nucleotides
Beta aminoisobutyrate
The β-alanine and β-aminoisobutyrate serve as NH2 donors in transamination of
α-ketoglutarate to glutamate
which can be diverted to fatty acid synthesis
Malonyl CoA
which is converted to succinyl-CoA and can be shunted to the TCA cycle
Methylmalonyl CoA
The salvage of pyrimidine bases has less clinical significance than that of the purines, owing to the solubility of the byproducts of pyrimidine catabolism
Nice to know
Uracil can be salvaged to form UMP through the concerted action of
Uridine phisphorylase
Uridine kinase
Formation of dTMP, by salvage of thymine requires
thymine phosphorylase and thymidine kinase
The salvage of deoxycytidine is catalyzed by
deoxycytidine kinase
Two inherited disorders affecting pyrimidine biosynthesis are the result of deficiencies in the bifunctional enzyme catalyzing the last two steps of UMP synthesis
orotate phosphoribosyl transferase and OMP decarboxylase
causes retarded growth, and severe anemia caused by hypochromic erythrocytes and megaloblastic bone marrow
Orotic aciduria
also common in orotic acidurias
Leukopenia
can also cause orotic aciduria because it can act as an alternate substrate and compete with orotic acid for degradation
Allopurinol
Orotic aciduria can be treated with
uridine and/or cytidine