Gouty Arthritis

A disease on nucleotide metabolism

Glycoly6 - Dornagon, Flores, Laki, Larracas, Supelana, Tejano

PhCh 127 - PHB
Outline

I. Journals Related to Gouty Arthritis and Nucleotide Metabolism

Single nucleotide polymorphisms associated with P2X7R function regulate the
onset of gouty arthritis
Physiological functions and pathogenic potential of uric acid: A review
Uric acid in plants and microorganisms: Biological applications and genetics -
A review
II. How was the Disease Discovered?
III. Nucleotide Metabolic Pathways
1 Single nucleotide polymorphisms associated with
P2X7R function regulate the onset of gouty arthritis
Gout is an inflammatory disease that is caused by the increased production of
(Tao, Cheng, Tang, Dai, Zhang, Li, & Wang, 2017)

Interleukin-1 (IL-1) stimulated by monosodium urate (MSU) crystals.

However, some hyperuricemia patients, even gouty patients with tophi in the
joints, never experience gout attack, which indicates that pathogenic pathways
other than MSU participate in the secretion of IL-1 in the pathogenesis of acute
gouty arthritis.
The ATP-P2X7R-IL-1 axis may be one of these pathways.
1 Single nucleotide polymorphisms associated with
P2X7R function regulate the onset of gouty arthritis

Objective: examine the

role of Adenosine triphosphate (ATP) in the pathogenesis of gout
association of ATP receptor (P2X7R) function with single nucleotide polymorphisms and
gout arthritis.
Methodology:
Non-synonymous single nucleotide polymorphisms (SNP) loci of P2X7R in Chinese
people were screened to compare the frequencies of different alleles and genotype
distribution of selective SNPs in 117 gouty patients and 95 hyperuricemia patients.
Peripheral white blood cells were purified from the peripheral blood of 43 randomly
selected gout patients and 36 hyperuricemia patients from the total group. Cells were
cultured with MSU or MSU + ATP, and supernatants were collected for the detection of
IL-1 concentrations using enzyme-linked immunosorbent assay (ELISA).
1 Single nucleotide polymorphisms associated with
P2X7R function regulate the onset of gouty arthritis

Results
1.Eight SNP loci, including rs1653624, rs10160951, rs1718119, rs7958316, rs16950860,
rs208294, rs17525809 and rs2230912, were screened and detected, and rs1653624,
rs7958316 and rs17525809 were associated with gout arthritis.
2.IL-1 concentrations in supernatants after MSU + ATP stimulation were significantly
higher in gouty patients than in the hyperuricemia group [(131.08 176.11) pg/ml
vs. (50.84 86.10) pg/ml]; Patients carrying the susceptibility genotype AA or AT of
rs1653624 exhibited significantly higher concentrations of IL-1 than patients
carrying the non-susceptibility genotype TT [(104.20 164.25) pg/ml vs. (21.90
12.14) pg/ml]; However, no differences were found with MSU stimulation alone.
2 Physiological functions and
pathogenic potential of uric acid: A review

(El Ridi, & Tallima, 2017)

Uric acid, mainly from animal food products, derives mainly from liver,
intestines, muscles, kidneys, and the vascular endothelium.
Cells degrade adenine and guanine into purines.
First, deamination and dephosphorylation into inosine and guanosine; then
nucleoside phosphorylase, hypoxanthine and guanine
Xanthine oxidase-oxidation of hypoxanthine and deamination of
guanine, forms uric acid.
Due to lack of uricase enzyme, humans cannot convert uric acid into
allantoin.
2 Physiological functions and
pathogenic potential of uric acid: A review

Gout is the deposition of crystals of monosodium urate (MSU) into joint, and not
simply high levels of uric acid in the blood.
MSU is coated in serum proteins to combine with cells surface, stimulating the
cytosolic molecular platform involved in innate immunity. MSU crystals are
endogenous signals formed after uric acid release from dying cells. Purines in the
DNA are converted to uric acid.
Though uric acid is soluble in blood up to 70g/ml, exceeding such levels do not
entirely produce MSU.
Defects in genes which produce urate-anion exchange transporter 1 (URAT 1) and
glucose transporter (Glut9) is seen to be precursors for MSU.
2 Physiological functions and
pathogenic potential of uric acid: A review

MSU deposits in connective tissue of joints, tendons, kidneys, and rarely heart
valves and pericardium and interact with serum proteins.
Then, macrophages, mast cells, neutrophils, monocytes, non-haemopoietic
synovial and endothelial cells for them to phago- or endocytose MSU to
release danger-associated molecular patterns (DAMP). The MSU also
damages the cells to release purines.
The sodium content, osmomolarity, water influx and potassium concentration
change. This produces a danger signal. Lytic form of cell death, pyroptosis, is
observed. MSU crystals need free fatty acids to induce gout. MSU crystals
induce more MSU-associated release of IL-1B by activating neutrophils. This
induce fever also destruction of music and cartilage.
2 Physiological functions and
pathogenic potential of uric acid: A review

Conclusion:
Uric acids contribution to gout and metabolic syndromes are well
established.
Uric acid is primarily for preservation of human species, but the
kidneys overcompensation due to lose of uricase causes
complications.
Yet, studies are still needed to study more impacts in infections,
neurological and autoimmune diseases.
3 Uric acid in plants and microorganisms: Biological
applications and genetics - A review

(Hafez, Abdel-Rahman, & Naguib, 2017)

Pathogenesis of gout, is closely related to increased accumulation and/or

reduced excretion of uric acid in human bodies.
Uric acid can be found in both higher plants and microorganisms with species
dependent concentration.
Occurrence of gout is highly affected by the high intake of food rich in purine.
In humans, researchers found that several mutations caused a pseudogenization
(silencing) of the uricase gene in ancestral apes which exist as an insoluble
crystalloid in peroxisomes.
This is in contrast to microorganisms in which uricases are soluble and exist either in
cytoplasm or peroxisomes.
3 Uric acid in plants and microorganisms: Biological
applications and genetics - A review

Both plants and microorganisms contain urate-degrading enzymes, but the

mechanisms by which plant degrade uric acid was found to be different
between them.
Higher plants produce various metabolites which could inhibit xanthine
oxidase and xanthine oxidoreductase, thus prohibiting the oxidation of
hypoxanthine to xanthine then to uric acid in the purine metabolism.
However, microorganisms produce group of degrading uricase,
allantoinase, allantoicase and urease, which catalyze the degradation of
uric acid to ammonia.
3 Uric acid in plants and microorganisms: Biological
applications and genetics - A review

Moreover, many recombinant uricases with higher activity than the wild
type uricases could be induced successfully in many microorganisms.
The present review deals with the occurrence of uric acid in plants and
other organisms especially microorganisms in addition to the mechanisms
by which plant extracts, metabolites and enzymes could reduce uric acid
in blood.
The genetic genes encoding for uric acid in plants and microorganisms are
also presented.
Summary of the Report

Gout is a type of inflammatory arthritis that is triggered by the

crystallization of uric acid within the joints and is often associated
with hyperuricemia.
Acute gout is typically intermittent, constituting one of the most
painful conditions experienced by humans.
Chronic tophaceous gout usually develops after years of acute
intermittent gout, although tophi occasionally can be part of the
initial presentation.
II. How was the disease discovered?
(Nuki & Simkin, 2006).
earliest diseases to be recognized as a clinical entity.
First identified by the Egyptians in 2640 BC, podagra
acute gout occurring in the first metatarsophalangeal joint)
later recognized by Hippocrates in the fifth century BC, who referred to it as 'the unwalkable
disease'.
The Latin word gutta (or drop) is where the term was derived, and referred to the
prevailing medieval belief that an excess of one of the four humors which in
equilibrium were thought to maintain health would, under certain
circumstances, 'drop' or flow into a joint, causing pain and inflammation.
Excessive alcohol consumption and rich foods has been associated with gout
throughout history. Referred to as disease of kings, because it is clearly
associated with a lifestyle that at that time, only the rich can afford.
II. How was the disease discovered?

Colchicine, an alkaloid derived from the autumn crocus (Colchicum autumnale),

its first use as a selective and specific treatment for gout
Byzantine Christian physician Alexander of Tralles in the sixth century AD
used as a powerful purgative in ancient Greece more than 2000 years ago
Uricosuric agents- first used at the end of the 19th century
Nonsteroidal anti-inflammatory drugs- drugs of choice for treating acute gout in
the modern era.
Perhaps the most important historical advance in the treatment of hyperuricemia
was the development of xanthine oxidase inhibitors, which are effective in
reducing plasma and urinary urate levels and have been shown to reverse the
development of tophaceous deposits (Nuki & Simkin, 2006).
III. Metabolic Pathways

Figure 1. Pentose-phosphate
pathway.
Figure 2. Nucleotide metabolism.
Figure 3. Production of adenosine monophosphate (AMP) and
guanosine monophosphate (GMP) as nucleotides.
Figure 4. Production of urates from the degradation of AMP and GMP.
Figure 5. Production of uric acd from the degradation of AMP and GMP.
Figure 6. Pathway for the production and degradation of nucleotides.
References
El Ridi, R., & Tallima, H. (2017). Physiological functions and pathogenic potential of
uric acid: A review. Journal of Advanced Research, 8(5), 487-493.
doi:10.1016/j.jare.2017.03.003
Hafez, R. M., Abdel-Rahman, T. M., & Naguib, R. M. (2017). Uric acid in plants and
microorganisms: Biological applications and genetics - A review. Journal of
Advanced Research, 8(5), 475486.
http://doi.org/10.1016/j.jare.2017.05.003
Nuki, G., & Simkin, P. A. (2006). A concise history of gout and hyperuricemia and their
treatment. Arthritis Research & Therapy, 8 (1). doi:10.1186/ar1906
Tao, J., Cheng, M., Tang, J., Dai, X., Zhang, Y., Li, X., & Wang, Y. (2017). Single
nucleotide polymorphisms associated with P2X7R function regulate the
onset of gouty arthritis.
Plos One, 12 (8). doi:10.1371/journal.pone.0181685