Nucleic acid
Nucleic acids are the polymer of nucleotides (polynucleotides) held by 3’ and 5’ phosphate bridge.
Nucleotide
Nucleotide perform variety of functions in a living cells. They are composed of pentose sugar, phosphate and a nitrogenous base.
Functions of Nucleotide
Monomeric units of DNA and RNA
Structural component of several coenzymes e.g. FAD, NADP+
Serve as carriers of high energy intermediates in the biosynthesis of carbohydrates, lipids and proteins
Nucleotides are intimately involved in the energy reactions of the cell e.g. ATP
Control several metabolic reactions by their action as allosteric regulators.
Cyclic AMP amd cyclic GMP are the second messenger in hormonal functions.
Nucleotide structure
Biosynthesis of Purines
Biosynthesis of Pyrimidine
Disorder of Purine
Catabolism of Purine
Nucleic acid
Nucleic acids are the polymer of nucleotides (polynucleotides) held by 3’ and 5’ phosphate bridge.
Nucleotide
Nucleotide perform variety of functions in a living cells. They are composed of pentose sugar, phosphate and a nitrogenous base.
Functions of Nucleotide
Monomeric units of DNA and RNA
Structural component of several coenzymes e.g. FAD, NADP+
Serve as carriers of high energy intermediates in the biosynthesis of carbohydrates, lipids and proteins
Nucleotides are intimately involved in the energy reactions of the cell e.g. ATP
Control several metabolic reactions by their action as allosteric regulators.
Cyclic AMP amd cyclic GMP are the second messenger in hormonal functions.
Nucleotide structure
Biosynthesis of Purines
Biosynthesis of Pyrimidine
Disorder of Purine
Catabolism of Purine
introduction of Purine and Pyrimidine metabolism, biosynthesis and degradation of nucleotides, biological functions and metabolic disorders, chemical analogues and therapeutic drugs, uric acid metabolism
The slide has some brief introduction to nucleotide chemistry, History, General features of nucleotides, Nomenclature, Individual properties of bases, Classification
and Synthetic analogues of biomedical importance.
introduction of Purine and Pyrimidine metabolism, biosynthesis and degradation of nucleotides, biological functions and metabolic disorders, chemical analogues and therapeutic drugs, uric acid metabolism
The slide has some brief introduction to nucleotide chemistry, History, General features of nucleotides, Nomenclature, Individual properties of bases, Classification
and Synthetic analogues of biomedical importance.
THE IMPORTANCE OF MARTIAN ATMOSPHERE SAMPLE RETURN.Sérgio Sacani
The return of a sample of near-surface atmosphere from Mars would facilitate answers to several first-order science questions surrounding the formation and evolution of the planet. One of the important aspects of terrestrial planet formation in general is the role that primary atmospheres played in influencing the chemistry and structure of the planets and their antecedents. Studies of the martian atmosphere can be used to investigate the role of a primary atmosphere in its history. Atmosphere samples would also inform our understanding of the near-surface chemistry of the planet, and ultimately the prospects for life. High-precision isotopic analyses of constituent gases are needed to address these questions, requiring that the analyses are made on returned samples rather than in situ.
Cancer cell metabolism: special Reference to Lactate PathwayAADYARAJPANDEY1
Normal Cell Metabolism:
Cellular respiration describes the series of steps that cells use to break down sugar and other chemicals to get the energy we need to function.
Energy is stored in the bonds of glucose and when glucose is broken down, much of that energy is released.
Cell utilize energy in the form of ATP.
The first step of respiration is called glycolysis. In a series of steps, glycolysis breaks glucose into two smaller molecules - a chemical called pyruvate. A small amount of ATP is formed during this process.
Most healthy cells continue the breakdown in a second process, called the Kreb's cycle. The Kreb's cycle allows cells to “burn” the pyruvates made in glycolysis to get more ATP.
The last step in the breakdown of glucose is called oxidative phosphorylation (Ox-Phos).
It takes place in specialized cell structures called mitochondria. This process produces a large amount of ATP. Importantly, cells need oxygen to complete oxidative phosphorylation.
If a cell completes only glycolysis, only 2 molecules of ATP are made per glucose. However, if the cell completes the entire respiration process (glycolysis - Kreb's - oxidative phosphorylation), about 36 molecules of ATP are created, giving it much more energy to use.
IN CANCER CELL:
Unlike healthy cells that "burn" the entire molecule of sugar to capture a large amount of energy as ATP, cancer cells are wasteful.
Cancer cells only partially break down sugar molecules. They overuse the first step of respiration, glycolysis. They frequently do not complete the second step, oxidative phosphorylation.
This results in only 2 molecules of ATP per each glucose molecule instead of the 36 or so ATPs healthy cells gain. As a result, cancer cells need to use a lot more sugar molecules to get enough energy to survive.
Unlike healthy cells that "burn" the entire molecule of sugar to capture a large amount of energy as ATP, cancer cells are wasteful.
Cancer cells only partially break down sugar molecules. They overuse the first step of respiration, glycolysis. They frequently do not complete the second step, oxidative phosphorylation.
This results in only 2 molecules of ATP per each glucose molecule instead of the 36 or so ATPs healthy cells gain. As a result, cancer cells need to use a lot more sugar molecules to get enough energy to survive.
introduction to WARBERG PHENOMENA:
WARBURG EFFECT Usually, cancer cells are highly glycolytic (glucose addiction) and take up more glucose than do normal cells from outside.
Otto Heinrich Warburg (; 8 October 1883 – 1 August 1970) In 1931 was awarded the Nobel Prize in Physiology for his "discovery of the nature and mode of action of the respiratory enzyme.
WARNBURG EFFECT : cancer cells under aerobic (well-oxygenated) conditions to metabolize glucose to lactate (aerobic glycolysis) is known as the Warburg effect. Warburg made the observation that tumor slices consume glucose and secrete lactate at a higher rate than normal tissues.
A brief information about the SCOP protein database used in bioinformatics.
The Structural Classification of Proteins (SCOP) database is a comprehensive and authoritative resource for the structural and evolutionary relationships of proteins. It provides a detailed and curated classification of protein structures, grouping them into families, superfamilies, and folds based on their structural and sequence similarities.
Slide 1: Title Slide
Extrachromosomal Inheritance
Slide 2: Introduction to Extrachromosomal Inheritance
Definition: Extrachromosomal inheritance refers to the transmission of genetic material that is not found within the nucleus.
Key Components: Involves genes located in mitochondria, chloroplasts, and plasmids.
Slide 3: Mitochondrial Inheritance
Mitochondria: Organelles responsible for energy production.
Mitochondrial DNA (mtDNA): Circular DNA molecule found in mitochondria.
Inheritance Pattern: Maternally inherited, meaning it is passed from mothers to all their offspring.
Diseases: Examples include Leber’s hereditary optic neuropathy (LHON) and mitochondrial myopathy.
Slide 4: Chloroplast Inheritance
Chloroplasts: Organelles responsible for photosynthesis in plants.
Chloroplast DNA (cpDNA): Circular DNA molecule found in chloroplasts.
Inheritance Pattern: Often maternally inherited in most plants, but can vary in some species.
Examples: Variegation in plants, where leaf color patterns are determined by chloroplast DNA.
Slide 5: Plasmid Inheritance
Plasmids: Small, circular DNA molecules found in bacteria and some eukaryotes.
Features: Can carry antibiotic resistance genes and can be transferred between cells through processes like conjugation.
Significance: Important in biotechnology for gene cloning and genetic engineering.
Slide 6: Mechanisms of Extrachromosomal Inheritance
Non-Mendelian Patterns: Do not follow Mendel’s laws of inheritance.
Cytoplasmic Segregation: During cell division, organelles like mitochondria and chloroplasts are randomly distributed to daughter cells.
Heteroplasmy: Presence of more than one type of organellar genome within a cell, leading to variation in expression.
Slide 7: Examples of Extrachromosomal Inheritance
Four O’clock Plant (Mirabilis jalapa): Shows variegated leaves due to different cpDNA in leaf cells.
Petite Mutants in Yeast: Result from mutations in mitochondrial DNA affecting respiration.
Slide 8: Importance of Extrachromosomal Inheritance
Evolution: Provides insight into the evolution of eukaryotic cells.
Medicine: Understanding mitochondrial inheritance helps in diagnosing and treating mitochondrial diseases.
Agriculture: Chloroplast inheritance can be used in plant breeding and genetic modification.
Slide 9: Recent Research and Advances
Gene Editing: Techniques like CRISPR-Cas9 are being used to edit mitochondrial and chloroplast DNA.
Therapies: Development of mitochondrial replacement therapy (MRT) for preventing mitochondrial diseases.
Slide 10: Conclusion
Summary: Extrachromosomal inheritance involves the transmission of genetic material outside the nucleus and plays a crucial role in genetics, medicine, and biotechnology.
Future Directions: Continued research and technological advancements hold promise for new treatments and applications.
Slide 11: Questions and Discussion
Invite Audience: Open the floor for any questions or further discussion on the topic.
Seminar of U.V. Spectroscopy by SAMIR PANDASAMIR PANDA
Spectroscopy is a branch of science dealing the study of interaction of electromagnetic radiation with matter.
Ultraviolet-visible spectroscopy refers to absorption spectroscopy or reflect spectroscopy in the UV-VIS spectral region.
Ultraviolet-visible spectroscopy is an analytical method that can measure the amount of light received by the analyte.
Professional air quality monitoring systems provide immediate, on-site data for analysis, compliance, and decision-making.
Monitor common gases, weather parameters, particulates.
1. Kwame Nkrumah University of
Science & Technology, Kumasi, Ghana
Purine Metabolism
(Biosynthesis and Catabolism)
2. LEARNING OUTCOMES
At the end of this lecture students should:
Understand nucleosides*, nucleotides, and their function in
DNA and RNA.
Understand the structure and function of purines.
Understand the origin of atoms in the purine ring.
Understand the essential features of purine metabolism and
catabolism.
Understand clinical aspects of purine metabolism and
deficiencies.
3. Nucleotides
Chemical compound composed of three components: (1)
heterocyclic base; (2) sugar (usually a pentose); and (3) one
or more phosphate groups
Adenosine monophosphate (AMP)
Base
Pentose sugar
Phosphate
Glycosidic bond
4. Nucleotides actively participate in many biochemical
reactions
ATP and GTP (nucleotides) are energy sources.
Uridine derivatives of sugars participate in carbohydrate
metabolism
Coenzymes (NAD, FAD, Co-A) are nucleotide
derivatives
[ATP], [ADP], [AMP] act as allosteric (Activation of
protein from other than active site) regulators of key
enzymes in nucleotide synthesis.
7. Important Notes about Nucleotides
Diet Nucleoprotein, purine and pyrimidine bases do not directly
incorporate in Nucleic acids synthesis. The human body synthesize
the nitrogenous bases for nucleic acid, ATP, NAD, Co-A from
Amphibolic intermediate.
Nucleoprotein from diet are digested in intestinal tract.
Nucleic acids are degraded with help of ribonucleases,
deoxyribonucleases, polynucleotidases to nucleotides. Furthermore,
it produces uric acid with the help of phosphorylase enzymes.
8. The Nitrogenous Bases
In DNA:
Adenine
Guanine
*Thymine*
Cytosine
In RNA:
Adenine
Guanine
*Uracil*
Cytosine
10. Two Important Points
1. The phosphate groups are
responsible for the net
negative charge associated
with DNA and RNA.
2. The hydroxyl group at the 2’-
position accounts for the
greater ease with which RNA is
degraded by alkali.
11. Mechanism of RNA Hydrolysis
Hydrolysis occurs by nucleophilic attack of the 2’-hydroxyl group on the
polarized phosphate to yield a 2’-3’ cyclic phosphodiester intermediate
(circled) that subsequently spontaneously hydrolyzes to a mix of 2’- and 3’-
phosphomonoesters.
12. Biosynthesis of Purine Nucleotide
All form of life synthesize the Purine even
Pyrimidine nucleotide except parasitic protozoa
Nucleotides can synthesize by
• De Novo pathway: Nucleotides are constructed from
simple precursors from metabolic process.
• Salvage pathways: Recovery and recycling of
nucleotides obtained in the diet
14. The Purine Ring
The purine ring is synthesized by a series of reactions that add
the carbon and nitrogen atoms to a pre-formed ribose-5-
phosphate.
The ribose-5-phosphate is synthesized as part of the Hexose
Monophosphate pathway.
In humans, all necessary enzymes are found in the cytoplasm of
the cell.
16. The pentose sugar is always a ribose, which may be reduced
to deoxyribose after nucleotide synthesis is complete.
5-Phosphoribosyl-1-pyrophosphate (PRPP) is also
involved in synthesis of pyrimidine nucleotides, NAD+, and
histidine biosynthesis.
Conversion of Ribose-5-phosphate to
PRPP
17. 1. First step of purine
synthesis is committed
step and rate limiting
step.
2. Intracellular concentrations
of glutamine and PRPP
control the reaction rate.
3. Inhibited by AMP, GMP,
and IMP.
4. Requires 4 ATP molecules.
De novo purine synthesis
19. Synthesis of Adenine and Guanine
Ribonucleotides
IMP does not accumulate in the cell but is rapidly converted to AMP
and GMP. In the first reaction, aspartate’s amino group is linked to
IMP in a reaction driven by the hydrolysis of GTP to GDP Pi to yield
adenylosuccinate.
In the second reaction, adenylosuccinate lyase eliminates
fumarate from adenylosuccinate to form AMP.This enzyme also
catalyzes Reaction 9 of the IMP pathway.
IMP dehydrogenase catalyzes the NAD-dependent oxidation of
IMP to form xanthosine monophosphate (XMP). XMP is then
converted to GMP by the replacement of its 2-keto group with
glutamine’s amide nitrogen in a reaction driven by the hydrolysis of
ATP to AMP Ppi.
20. Synthesis of ADP, ATP, GDP and GTP
Corresponding nucleoside triphosphates are required for the synthesis of Nucleic
acid.
In phosphorylation reactions respective nucleoside monophosphate are
synthesized in presence of base specific nucleoside monophosphate kinases.
These enzymes do not discriminate between ribose and deoxyribose in the
substrate.
Adenylate kinase is particularly active in the liver and in muscle, where the
turnover of energy from ATP is high.
21. Dug effects on Folates and Tetrahydrofolic acid
synthesis
22. Sulfonamides inhibit purine synthesis in bacteria by interfering with folate
synthesis.
That methotrexate inhibits purine synthesis by inhibiting dihydrofolate
reductase.
AMP, GMP, and IMP inhibit the reaction in the rate limiting step while
PRPP is an activator.
Para-aminobenzoic acid (PABA) is not directly involved in the de novo
synthesis of purines but plays a crucial role in the biosynthesis of another
important group of compounds called folates or folic acid.
Folates are essential cofactors in various cellular processes, including
the de novo synthesis of purines and pyrimidines, as well as in various
one-carbon transfer reactions crucial for nucleotide synthesis,
methylation reactions, and DNA synthesis.
Other Effects on Purine metabolism
24. Salvage pathway
In the salvage pathway, purine bases produced by degradation of RNA or
DNA and intermediate of purine synthesis can be directly converted to the
corresponding nucleotides.
The salvage pathway mainly involves the conversion of free purine bases
into their corresponding nucleotides using phosphoribosyl pyrophosphate
(PRPP) as a co-substrate.
The key steps in the salvage pathway of purine biosynthesis are as follows:
Uptake of Purine Bases: Cells can obtain free purine bases from various
sources, including the breakdown of nucleic acids (e.g., DNA and RNA)
during cell turnover and the diet. Purine bases, such as adenine, guanine,
and hypoxanthine, can enter the cell through specific transporters.
Phosphoribosylation: Once inside the cell, the free purine bases are
converted into nucleotides through the action of specific enzymes called
phosphoribosyltransferases. These enzymes transfer the 5-phosphoribosyl
group from PRPP to the purine base, resulting in the formation of the
corresponding nucleotide.
25. Two phosphoribosyl transferases are involved
in salvage pathway
APRT (adenine phosphoribosyl transferase) for adenine to form
AMP
HGPRT (hypoxanthine guanine phosphoribosyl transferase) for
guanine or hypoxanthine
The significance of salvage pathway
Save the fuel.
Some tissues and organs such as brain and bone marrow are only
capable of synthesizing nucleotides by salvage pathway
Salvage pathway
26.
27. Lesch-Nyhan syndrome
First described in 1964 by Michael Lesch and William L. Nyhan.
There is a defect or lack in the Hypoxanthine-Guanine
phosphoribosyl transferase (HGPRT) enzyme encoded by HPRT1
gene
A defect may be in the production or activity of HGPRT
Causes increased level of Hypoxanthine and Guanine (in
degradation to uric acid)
Sex-linked (X-linked) metabolic disorder: only males
The prevalence is approximately 1 in 380,000
Mutations in the HPRT1 gene
28. The rate of purine synthesis is increased about 200-fold
Loss of HGPRT leads to elevated PRPP levels and
stimulation of de novo purine synthesis.
Uric acid level rises and there is gout disease
In addition there are mental aberrations or changes
Patients will self-mutilate by biting lips and fingers off
Lesch-Nyhan syndrome
29. Build up of hypoxanthine and guanine
Degradation of hypoxanthine and guanine results in increased uric acid
Excess uric acid in urine often results in orange crystals in the diaper of affected
children.
Severe mental retardation
Self-mutilation
Involuntary movements
Gout
Lesch-Nyhan Syndrome
30. Autism
About 25% of autistic persons may have purines at high
levels.
So purine test is a diagnostic test for autistic patients
o Biochemical findings from this test disappear
adolescence ( between 13-19 age).
o Must obtain urine specimen in infancy, but it’s may
difficult to do!
oPink urine due to uric acid crystals may be seen in
diapers
33. Purine Catabolism and Salvage
All purine degradation leads to uric acid
Ribonucleases, Deoxyribonucleases, Polynucleotidases
degrade the nucleic acids.
Ingested nucleic acids are degraded to nucleotides in
intestine
Pancreatic nucleases
Intestinal phosphodiesterases
Group-specific nucleotidases and non-specific
phosphatases degrade nucleotides into nucleoside
Direct absorption of nucleosides
Further degradation
34. Nucleosidase (Hydrolysis reactions)
The is intracellular reaction
Nucleoside + H2O base + ribose
n. Phosphorylase
Nucleoside + Pi base + r-1-phosphate
Importantly, Most of the ingested nucleic acids are
degraded and excreted
35. Intracellular Purine Catabolism
Nucleotides broken into nucleosides by action of
nucleotidase (Hydrolysis reactions)
Purine nucleoside phosphorylase (PNP)
Inosine to Hypoxanthine
Xanthosine to Xanthine
Guanosine to Guanine
36. Intracellular Purine Catabolism
Xanthine is the point of convergence for the
metabolism of the purine bases
Xanthine converted to Uric acid
Xanthine oxidase catalyzes two reactions
Purine ribonucleotide (In case of RNA) degradation
pathway is same for purine deoxyribonucleotides (In
case of DNA)
39. Uric acid is the excreted end product of purine catabolism in
primates, birds, and some other animals.
The rate of uric acid excretion by the normal adult human is
about 0.6 g/24 h, arising in part from ingested purines and in
part from the turnover of the purine nucleotides of nucleic
acids.
The normal concentration of uric acid in the serum of adults
is in the range of 3-7 mg/dl.
Uric acid
40. Gout is a disease of the joints, usually in males, caused by
an elevated concentration of uric acid in the blood and
tissues.
The joints become inflamed, painful, and arthritic, owing to
the abnormal deposition of crystals of sodium urate.
The kidneys are also affected, because excess uric acid is
deposited in the kidney tubules
GOUT
41. dATP builds up and inhibits
ribonucleotide reductase.
Inhibition of ribonucleotide reductase results in no dNDP being produced.
No synthesis of DNA in lymphocytes results in Severe Combined
Immunodeficiency Syndrome (SCIDS).
XMP
Xanthosine
42. Gout
Characterized by hyperuricemia and acute arthritic joint
inflammation by deposition of uric acid crystals
Primary gout is genetic and mainly affects men over 30
Secondary gout is associated with leukemia, polycythemia,
HGPRT deficiency, renal insufficiency, lifestyle (rich foods).
45. Drugs That Promote Gout
Certain drugs can cause secondary gout due to actions
on the kidney that affect uric acid reabsorption,
secretion, and excretion.
– Diuretics, due to their actions on the kidney, can
increase uric acid reabsorption and lead to
hyperuricemia and resultant gout. Since recent data
has linked hypertension and hyperuricemia, initial
serum urate levels are an important consideration
when prescribing diuretics (especially thiazides) to
control blood pressure in order to avoid elevating urate
even further.
46. Drugs That Promote Gout
Caspi et al. Arth Rheum. 43, 103-108 (2000)
High doses of aspirin (>3 g/day) are uricosuric. Low doses, however, cause
uric acid retention. Caspi et al studied the effects of mini-dose aspirin,
utilized as a platelet inhibitor, on uric acid. The study found that doses as
low as 75 mg/day increased serum urate.
This indicates that elevated serum urate may be a problem in the large
population of patients that take mini-dose aspirin for this purpose. In
addition, these patients are often elderly with compromised renal
function, and they obtain this therapy over-the-counter.
Pyrazinamide, ethambutol, and niacin are other agents associated with
gout because they suppress uric acid secretion.