Thymidylate synthase
Short name=TS
Short name=TSase
EC=2.1.1.45
- Function
- Contributes to the de novo mitochondrial thymidylate biosynthesis pathway. Ref.13
- Catalytic activity
- 5,10-methylenetetrahydrofolate + dUMP = dihydrofolate + dTMP. HAMAP-Rule MF_00008
- Pathway
- Pyrimidine metabolism; dTTP biosynthesis. HAMAP-Rule MF_00008
- Subunit structure
- Homodimer.
- Subcellular location
- Nucleus. Cytoplasm. Mitochondrion. Mitochondrion matrix. Mitochondrion inner membrane
Dihydrofolate reductase
EC=1.5.1.3
- Function
- Key enzyme in folate metabolism. Contributes to the de novo mitochondrial thymidylate biosynthesis pathway. Catalyzes an essential reaction for de novo glycine and purine synthesis, and for DNA precursor synthesis. Binds its own mRNA and that of DHFRL1. Ref.9 Ref.16
- Catalytic activity
- 5,6,7,8-tetrahydrofolate + NADP+ = 7,8-dihydrofolate + NADPH. Ref.8 Ref.15 Ref.16 Ref.19 Ref.22 Ref.23 Ref.24
- Pathway
- Cofactor biosynthesis; tetrahydrofolate biosynthesis; 5,6,7,8-tetrahydrofolate from 7,8-dihydrofolate: step 1/1.
- Subunit structure
- Homodimer.
- Tissue specificity
- Widely expressed in fetal and adult tissues, including throughout the fetal and adult brains and whole blood. Expression is higher in the adult brain than in the fetal brain.
- Involvement in disease
- Megaloblastic anemia due to dihydrofolate reductase deficiency (DHFRD) [MIM:613839]: An inborn error of metabolism, characterized by megaloblastic anemia and/or pancytopenia, severe cerebral folate deficiency, and cerebral tetrahydrobiopterin deficiency. Clinical features include variable neurologic symptoms, ranging from severe developmental delay and generalized seizures in infancy, to childhood absence epilepsy with learning difficulties, to lack of symptoms.
- Note
- The disease is caused by mutations affecting the gene represented in this entry. Ref.6 Ref.26
- Sequence similarities
- Belongs to the dihydrofolate reductase family. Contains 1 DHFR (dihydrofolate reductase) domain.
- Biophysicochemical properties
- Kinetic parameters:KM=2.7 µM for dihydrofolate / KM=4.0 µM for NADPH
Serine hydroxymethyltransferase, cytosolic
Short name=SHMT
EC=2.1.2.1
Alternative name(s):
Glycine hydroxymethyltransferase
Serine methylase
- Function
- Interconversion of serine and glycine. HAMAP-Rule MF_00051
- Catalytic activity
- 5,10-methylenetetrahydrofolate + glycine + H2O = tetrahydrofolate + L-serine. HAMAP-Rule MF_00051
- Cofactor
- Pyridoxal phosphate.
- Pathway
- One-carbon metabolism; tetrahydrofolate interconversion. HAMAP-Rule MF_00051
- Subunit structure
- Homotetramer.
- Subcellular location
- Cytoplasm HAMAP-Rule MF_00051.
- Miscellaneous
- In eukaryotes there are two forms of the enzymes: a cytosolic one and a mitochondrial one.
Sequence similarities
Belongs to the SHMT family.
Deoxycytidylate deaminase
- http://www.uniprot.org/uniprot/P32321
- EC=3.5.4.12
- Alternative name(s)
- dCMP deaminase
- Function
- Supplies the nucleotide substrate for thymidylate synthetase.
- Catalytic activity
- dCMP + H2O = dUMP + NH3.
- Cofactor
- Zinc.
- Enzyme regulation
- Allosteric enzyme whose activity is greatly influenced by the end products of its metabolic pathway, dCTP and dTTP.
- Subunit structure
- Homohexamer.
- Sequence similarities
- Belongs to the cytidine and deoxycytidylate deaminase family.
DNA dC->dU-editing enzyme APOBEC-3G
- http://www.uniprot.org/uniprot/Q9HC16
- EC=3.5.4.-
- Alternative name(s)
- APOBEC-related cytidine deaminase (Short name=APOBEC-related protein / Short name=ARCD) / APOBEC-related protein 9 (Short name=ARP-9) / CEM-15 (Short name=CEM15) / Deoxycytidine deaminase (Short name=A3G)
- Function
- DNA deaminase (cytidine deaminase) which acts as an inhibitor of retrovirus replication and retrotransposon mobility via deaminase-dependent and -independent mechanisms. Exhibits potent antiviral activity against vif-deficient HIV-1. After the penetration of retroviral nucleocapsids into target cells of infection and the initiation of reverse transcription, it can induce the conversion of cytosine to uracil in the minus-sense single-strand viral DNA, leading to G-to-A hypermutations in the subsequent plus-strand viral DNA. The resultant detrimental levels of mutations in the proviral genome, along with a deamination-independent mechanism that works prior to the proviral integration, together exert efficient antiretroviral effects in infected target cells. Selectively targets single-stranded DNA and does not deaminate double-stranded DNA or single-or double-stranded RNA. Exhibits antiviral activity also against simian immunodeficiency viruses (SIVs), hepatitis B virus (HBV), equine infectious anemia virus (EIAV), xenotropic MuLV-related virus (XMRV) and simian foamy virus (SFV). May inhibit the mobility of LTR and non-LTR retrotransposons. Ref.1 Ref.10 Ref.11 Ref.12 Ref.13 Ref.14 Ref.15 Ref.18 Ref.23 Ref.24 Ref.26 Ref.33 Ref.35 Ref.36 Ref.40 Ref.41 Ref.46 Ref.48 Ref.49 Ref.52 Ref.53 Ref.54
- Catalytic activity
- Deoxycytidine + H2O = deoxyuridine + NH3. Ref.13 Ref.54 Ref.55 Ref.56
- Cofactor
- Zinc.
- Enzyme regulation
- Assembly into ribonucleoprotein complexes of high-molecular-mass (HMM) inhibits its enzymatic activity. Antiviral activity is neutralized by the HIV-1 virion infectivity factor (VIF), that prevents its incorporation into progeny HIV-1 virions by both inhibiting its translation and/or by inducing its ubiquitination and subsequent degradation by the 26S proteasome. Can also be neutralized by simian immunodeficiency virus sooty mangabey monkey virus (SIV-sm) and chimpanzee immunodeficiency virus (SIV-cpz) VIF. Ref.41
- Subunit structure
- Homodimer. Homooligomer. Can bind RNA to form ribonucleoprotein complexes of high-molecular-mass (HMM) or low-molecular-mass (LMM). HMM is inactive and heterogeneous in protein composition because of binding nonselectively to cellular RNAs, which in turn are associated with variety of cellular proteins. The LMM form which is enzymatically active has few or no RNAs associated. Its ability to form homooligomer is distinct from its ability to assemble into HMM. Interacts with APOBEC3B, APOBEC3F, MOV10, AGO2, EIF4E, EIF4ENIF1, DCP2 and DDX6 in an RNA-dependent manner. Interacts with AGO1, AGO3 and PKA/PRKACA. Interacts with HIV-1 VIF and reverse transcriptase/ribonuclease H. Interacts with hepatitis B virus capsid protein. Ref.9 Ref.14 Ref.16 Ref.17 Ref.25 Ref.27 Ref.30 Ref.32 Ref.38 Ref.46 Ref.47 Ref.48
- Subcellular location
- Cytoplasm. Nucleus. Cytoplasm › P-body. Note: Mainly cytoplasmic. Small amount are found in the nucleus. During HIV-1 infection, virion-encapsidated in absence of HIV-1 VIF. Ref.11 Ref.24 Ref.27 Ref.31 Ref.39 Ref.41 Ref.48
- Tissue specificity
- Expressed in spleen, testes, ovary and peripheral blood leukocytes and CD4+ lymphocytes. Also expressed in non-permissive peripheral blood mononuclear cells, and several tumor cell lines; no expression detected in permissive lymphoid and non-lymphoid cell lines. Exists only in the LMM form in peripheral blood-derived resting CD4 T-cells and monocytes, both of which are refractory to HIV-1 infection. LMM is converted to a HMM complex when resting CD4 T-cells are activated or when monocytes are induced to differentiate into macrophages. This change correlates with increased susceptibility of these cells to HIV-1 infection. Ref.9 Ref.10 Ref.37
- Induction
- Up-regulated by IFN-alpha. Ref.15 Ref.41
- Domain
- The CMP/dCMP deaminase zinc-binding 1 domain mediates RNA binding, RNA-dependent oligomerization and virion incorporation whereas the CMP/dCMP deaminase zinc-binding 2 domain confers deoxycytidine deaminase activity and substrate sequence specificity (Ref.25). Ref.25 Ref.43
- Post-translational modification
- Ubiquitinated in the presence of HIV-1 VIF. Association with VIF targets the protein for proteolysis by the ubiquitin-dependent proteasome pathway. Ref.16 Ref.17 Ref.18
Phosphorylation at Thr-32 reduces its binding to HIV-1 VIF and subsequent ubiquitination and degradation thus promoting its antiviral activity.
- Miscellaneous
- Accumulation of APOBEC3G induced non-lethal hypermutation could contribute to the genetic variation of primate lentiviral populations.
It is one of seven related genes or pseudogenes found in a cluster, thought to result from gene duplication, on chromosome 22.
- Sequence similarities
- Belongs to the cytidine and deoxycytidylate deaminase family. Contains 2 CMP/dCMP deaminase zinc-binding domains.
