Department of Biochemistry Zhihong Li（李志红） Department of Biochemistry

Main Topics Metabolism of Nucleotides (4h) DNA replication(4h); RNA transcription(4h); Protein synthesis (4h) Gene expression and regulation (4h); Recombinant DNA technology (4h) Signal transduction(4h); Oncogene(2h); Gene and disease (2h) Diabetes mellitus (2h); Lipoproteins Metabolism (4h) Cholesterol Metabolism (2h); Bile acids Metabolism (2h) Plasma Proteins and Immuno Proteins (2h) Inter-assesment Free Radicals and Antioxidants (2h) ; Mineral Metabolism(2h) Water and Electrolyte Balance(2h); Acid Base Balance (2h) Heme Synthesis (2h); Bile Pigments Metabolism (2h) Liver function tests (2h); Metabolism of xenobiotics (2h) Hormones (6h); Biochemical changes during Pregnancy (2h) Biochemistry of Cerebrospinal fluid(CSF)(2h)

Lecture 1 Metabolism of Nucleotides

Contents Review: Structure of nucleic acid Degradation of nucleic acid Synthesis of Purine Nucleotides Degradation of Purine Nucleotides Synthesis of Pyrimidine Nucleotides Degradation of Pyrimidine Nucleotides

Nucleoside and Nucleotide Nitrogenous base ribose Nitrogenous base ribose phosphate

Purines vs Pyrimidines

Structure of nucleotides pyrimidine OR purine Ribose or 2-deoxyribose N-b-glycosyl bond

Section 1 Degradation of nucleic acid

Degradation of nucleic acid Nucleoprotein In stomach Gastric acid and pepsin Nucleic acid Protein In small intestine Endonucleases: RNase and DNase Nucleotide Nucleotidase Phosphate Nucleoside Nucleosidase Base Ribose

Lesch-Nyhan syndrome

Section 3 Degradation of Purine Nucleotides

The end product of purine metabolism (2,6,8-trioxypurine) Adenosine Deaminase The end product of purine metabolism (2,6,8-trioxypurine)

Uric acid 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.

GOUT The disease 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.

The uric acid and the gout Hypoxanthine Xanthine Out of body In urine Uric acid  Over 8mg/dl, in the plasma Diabetese nephrosis …… Gout, Urate crystallization in joints, soft tissue, cartilage and kidney

Advanced Gout Clinically Apparent Tophi 1 2 1 3 The advanced gout stage is often referred to as chronic tophaceous gout to indicate the presence of this clinical manifestation, which will remain unresolved in the absence of urate-lowering therapy. Tophi are characterized by solid urate deposits in connective tissues that produce irregular nodularities and joint destruction. In addition, the skin overlying the tophi may become ulcerated and exude a white, chalky material. Shown here are some common sites of tophi, including dermal tophi on the finger, periarticular tophi on the hands, and tophi on the helix of the ear. The patient who was experiencing the intradermal tophi on the knees was diagnosed and treated by multiple generalists and specialists for osteoarthritis. This photo was taken during his self-referred first visit to a rheumatologist and reinforces the point that gout is a disease that is under-recognized.1 The patient with polyarticular involvement of his hands had been misdiagnosed and treated for rheumatoid arthritis for 8 years.2 The tophi exhibited on this slide are clinically apparent, but this may not always be the case, as was seen in the previous case study examples of the tophi that formed in the bone of the knee and the palm of the hand. 1. Patient case study courtesy of Brian Mandell, MD, PhD, Cleveland Clinic. 2. Patient case study courtesy of N. Lawrence Edwards, MD, University of Florida. 1. Photos courtesy of Brian Mandell, MD, PhD, Cleveland Clinic. 2. Photo courtesy of N. Lawrence Edwards, MD, University of Florida. 3. ACR Clinical Slide Collection on the Rheumatic Diseases, 1998. 17

Points Synthesis of Purine Nucleotides De novo synthesis: Site, Characteristics, Element sources of purine bases Salvage pathway: definition, significance, enzyme, Lesch-Nyhan syndrome Formation of deoxyribonucleotide: NDP level Antimetabolites of purine nucleotides: Purine, Amino acid, and Folic acid analogs Degradation of Purine Nucleotides Uric acid, gout Synthesis of Pyrimidine Nucleotides De novo synthesis: Characteristics, Element sources of pyrimidine bases Salvage pathway Antimetabolites of pyrimidine nucleotides Catabolism of Pyrimidine Nucleotides