BH4 (6R-L-erythro-5,6,7,8-tetrahydrobiopterin) is an essential cofactor of a set of enzymes that are of central metabolic importance, including four aromatic amino acid hydroxylases, alkylglycerol mono-oxygenase and three NOS (NO synthase) isoenzymes. Consequently, BH4 is present in probably every cell or tissue of higher organisms and plays a key role in a number of biological processes and pathological states associated with monoamine neurotransmitter formation, cardiovascular and endothelial dysfunction, the immune response and pain sensitivity. BH4 is formed de novo from GTP via a sequence of three enzymatic steps carried out by GTP cyclohydrolase I, 6-pyruvoyltetrahydropterin synthase and sepiapterin reductase. An alternative or salvage pathway involves dihydrofolate reductase and may play an essential role in peripheral tissues. Cofactor regeneration requires pterin-4a-carbinolamine dehydratase and dihydropteridine reductase, except for NOSs, in which the BH4 cofactor undergoes a one-electron redox cycle without the need for additional regeneration enzymes. With regard to the regulation of cofactor biosynthesis, the major controlling point is GTP cyclohydrolase I. BH4 biosynthesis is controlled in mammals by hormones and cytokines. BH4 deficiency due to autosomal recessive mutations in all enzymes, except for sepiapterin reductase, has been described as a cause of hyperphenylalaninaemia. A major contributor to vascular dysfunction associated with hypertension, ischaemic reperfusion injury, diabetes and others, appears to be an effect of oxidized BH4, which leads to an increased formation of oxygen-derived radicals instead of NO by decoupled NOS. Furthermore, several neurological diseases have been suggested to be a consequence of restricted cofactor availability, and oral cofactor replacement therapy to stabilize mutant phenylalanine hydroxylase in the BH4-responsive type of hyperphenylalaninaemia has an advantageous effect on pathological phenylalanine levels in patients.

Tetrahydrobiopterin: biochemistry and pathophysiology.

William Carroll and colleagues report the identification of mutations in NT5C2, encoding cytosolic 5′-nucleotidase II, which are specific for relapsed childhood acute lymphoblastic leukemia. The mutations confer increased enzymatic activity and resistance to treatment with nucleoside analog therapies in vitro.

/pdf/relapse-specific-mutations-in-nt5c2-in-childhood-acute-nbyatlo5vq.pdf

Relapse-specific mutations in NT5C2 in childhood acute lymphoblastic leukemia.

Purpose: The goal of this study was to identify and validate novel serum markers of human colorectal cancer as potential candidates for noninvasive detection of early colorectal neoplasm. Experimental Design: Employing two-dimensional gel electrophoresis and mass spectrometry, we analyzed 16 matched colorectal cancer and adjacent normal tissue samples. Proteins found to be elevated in cancer tissue were further validated by generating antibodies which were used for immunoblotting of tissue samples and for the development of highly sensitive immunoassays for assessment of serum samples. Results: In total, 735 different proteins were identified in colon tissue. Strong elevation in colorectal cancer for five proteins was confirmed by immunoblot analysis: transforming growth factor-β induced protein ig-h3 (βIG-H3), nicotinamide N -methyltransferase (NNMT), nucleoside diphosphate kinase A (nm23-H1), purine nucleoside phosphorylase (PNPH), and mannose-6-phosphate receptor binding protein 1 (M6P1). Elevated levels of NNMT, which is not predicted to be secreted but is known as a cytoplasmic protein, were found in serum from patients with colorectal cancer. Employing a receiver-operating characteristic curve based on the measurement of 109 patients with colorectal cancer and 317 healthy controls, we obtained an area under the curve of 0.84 for NNMT, which was superior to the established tumor marker carcinoembryogenic antigen with an area under the curve of 0.78. Conclusions: It is proposed that NNMT serum levels may have significance in the early detection and in the management of patients with colorectal cancer.

https://clincancerres.aacrjournals.org/content/clincanres/11/18/6550.full.pdf

Identification of Nicotinamide N-Methyltransferase as a Novel Serum Tumor Marker for Colorectal Cancer

Altered extracellular ATP, ADP and AMP catabolism in glioma cell lines

Sepiapterin reductase catalyses the last steps in the biosynthesis of tetrahydrobiopterin, the essential co‐factor of aromatic amino acid hydroxylases and nitric oxide synthases. We have determined the crystal structure of mouse sepiapterin reductase by multiple isomorphous replacement at a resolution of 1.25 A in its ternary complex with oxaloacetate and NADP. The homodimeric structure reveals a single‐domain α/β‐fold with a central four‐helix bundle connecting two seven‐stranded parallel β‐sheets, each sandwiched between two arrays of three helices. Ternary complexes with the substrate sepiapterin or the product tetrahydrobiopterin were studied. Each subunit contains a specific aspartate anchor (Asp258) for pterin‐substrates, which positions the substrate side chain C1′‐carbonyl group near Tyr171 OH and NADP C4′N. The catalytic mechanism of SR appears to consist of a NADPH‐dependent proton transfer from Tyr171 to the substrate C1′ and C2′ carbonyl functions accompanied by stereospecific side chain isomerization. Complex structures with the inhibitor N ‐acetyl serotonin show the indoleamine bound such that both reductase and isomerase activity for pterins is inhibited, but reaction with a variety of carbonyl compounds is possible. The complex structure with N ‐acetyl serotonin suggests the possibility for a highly specific feedback regulatory mechanism between the formation of indoleamines and pteridines in vivo .

/pdf/the-1-25-a-crystal-structure-of-sepiapterin-reductase-59tc7i0i1o.pdf

The 1.25 A crystal structure of sepiapterin reductase reveals its binding mode to pterins and brain neurotransmitters.

The enzymatic pattern of five enzymes involved in the purine salvage pathway, namely purine nucleoside phosphorylase (EC 2.4.2.1), adenosine deaminase (EC 3.5.4.4), 5'-nucleotidase (EC 3.1.3.5), alkaline phosphatase (EC 3.1.3.1), and hypoxanthine-guanine phosphoribosyltransferase (EC 2.4.2.8) has been evaluated both in human intestinal and breast carcinomas and compared to that of normal tissues. A higher level of hypoxanthine-guanine phosphoribosyltransferase was associated with tumor tissues. This metabolic alteration should lead to an elevated synthesis of nucleotides in cancer cells, might confer selective growth advantages to neoplastic tissues, and account, at least in part, for the difficulties encountered in the chemotherapy of human tumors, by using compounds affecting only the purine de novo biosynthesis.

Purine salvage enzyme activities in normal and neoplastic human tissues.

Cytosolic 5′-nucleotidase acting preferentially on IMP and GMP has been purified from many sources1,2,3. The enzyme resulted to be allosterically activated by ATP, ADP and 2,3-diphosphoglycerate and inhibited by phosphate. Cytosolic 5′-nucleotidase appears to be widely distributed in mammalian tissues suggesting that it may have an essential function in cell metabolism. Furthermore the enzyme activity appears to be higher in tissues in active DNA synthesis or with a high turnover rate of nucleic acids and their precursors4.

Cytosolic 5'-nucleotidase/phosphotransferase of human colon carcinoma.

8-azaguanosine-5'-monophosphate synthesis via nucleoside kinase in cultured Chinese hamster lung fibroblasts.

8-Azaguanosine 14C-labeled in the ribose moiety was enzymatically synthesized in two steps: 1) phosphorolytic cleavage of [U-14C]inosine to yield [U-14C]ribose-1-phosphate; 2) synthesis of 8-azaguanosine from [U-14C]ribose-1-phosphate and 8-azaguanine catalyzed by purine nucleoside phosphorylase The radiochemical yield was 70%, and no contaminants were present in the isolated radioactive nucleoside analog, as judged by HPLC analysis

Enzymatic synthesis of [ribose-U-14C]8-azaguanosine

Substrates and/or Inhibitors of IMP-GMP Specific Cytosolic 5′-Nucleotidase (cN-II)

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