University of the Philippines Manila

College of Pharmacy
Department of Pharmaceutical Chemistry

GOUTY ARTHRITIS:
A Journal Summary Report

In partial fulfilment of the requirements for

Ph Ch 127: Pharmaceutical Biochemistry

Section PHB
Group Glycoly6

DORNAGON, Rhoen
FLORES, Richanela
LAKI, Miguel Pedro
LARRACAS, Jealaine
SUPELANA. Jewill
TEJANO, Amanda Beiya
 Outline

I. Journals Related to Gouty Arthritis

a. Single nucleotide polymorphisms associated with P2X7R function regulate the

onset of gouty arthritis
b. Physiological functions and pathogenic potential of uric acid: A review
c. Uric acid in plants and microorganisms: Biological applications and genetics -
A review

II. How was the Disease Discovered?

III. Nucleotide Metabolic Pathways

IV. Summary Report

V. References
I. Journals Related to Gouty Arthritis

JOURNAL NO. 1
Journal Title:
Single nucleotide polymorphisms associated with P2X7R function regulate the onset of gouty
arthritis
(Tao, Cheng, Tang, Dai, Zhang, Li, & Wang, 2017)
Summary:
Gout is an inflammatory disease that is caused by the increased production of 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.
This study examines the role of Adenosine triphosphate (ATP) in the pathogenesis of gout
and the association of ATP receptor (P2X7R) function with single nucleotide polymorphisms and
gout arthritis.
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).
Results found out that: 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 (including
gout and hyperuricemia) 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.
Therefore, ATP promotes the pathogenesis of gouty arthritis via increasing the secretion
of IL-1 , and its receptor (P2X7R) function associated single nucleotide polymorphisms may be
related to gouty arthritis, which indicates that ATP-P2X7R signaling pathway plays a significant
regulatory role in the pathogenesis of gout.

JOURNAL NO. 2
Journal Title:
Physiological functions and pathogenic potential of uric acid: A review
(El Ridi, & Tallima, 2017)
Summary:
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.
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
turned 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. 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.
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.

JOURNAL NO. 3
Journal Title:
Uric acid in plants and microorganisms: Biological applications and genetics - A review
(Hafez, Abdel-Rahman, & Naguib, 2017)
Summary:
Pathogenesis of gout, a complex form of arthritis and hyperuricemia 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. 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. 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.
II. How was Gouty Arthritis Discovered?

Gouty arthritis was among the 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) was 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. Although there is
evidence that colchicine, an alkaloid derived from the autumn crocus (Colchicum autumnale), was
used as a powerful purgative in ancient Greece more than 2000 years ago, its first use as a selective
and specific treatment for gout is attributed to the Byzantine Christian physician Alexander of
Tralles in the sixth century AD. Uricosuric agents were first used at the end of the 19th century.
Nonsteroidal anti-inflammatory drugs are usually the 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. Nucleotide Metabolic Pathways
IV. Summary Report
Uric acid, mainly from animal food products, derives mainly from liver, intestines,
muscles, kidneys, and the vascular endothelium. Cells degrade adenine and guanine by
deamination and dephosphorylation into inosine and guanosine, then nucleoside phosphorylase,
hypoxanthine and guanine. Xanthine oxidase-oxidation of hypoxanthine and deamination of
guanine eventually forms uric acid. Due to lack of uricase enzyme, humans cannot convert uric
acid into allantoin (El Ridi, & Tallima, 2017).
Gout is the deposition of crystals of monosodium urate (MSU) into joint, and not simply
due to 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. 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 and also destruction of music and cartilage.
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. 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. Moreover, many
recombinant uricases with higher activity than the wild type uricases could be induced successfully
in many microorganisms. The occurrence of uric acid in plants and microorganisms in addition to
the mechanisms by which plant extracts, metabolites and enzymes reduce uric acid in blood (Hafez
et al., 2017).

In addition, a study conducted by Tao et al. proved that ATP promotes the pathogenesis of
gouty arthritis via increasing the secretion of IL-1 , and its receptor (P2X7R) function associated
single nucleotide polymorphisms may be related to gouty arthritis, which indicates that ATP-
P2X7R signaling pathway plays a significant regulatory role in the pathogenesis of gout.

V. 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