| CTP is synthesized from UTP
|
| SEVERE COMBINED IMMUNODEFICIENCY SYNDROMES (SCIDS) |
SCIDS are a group of fatal disorders resulting from defects in both cellular and humoral immune function (see Chapter 36). SCIDS patients cannot efficiently produce antibodies in response to an antigenic challenge. Approximately 50% of patients with the autosomal recessive form of SCIDS have a genetic deficiency in the purine salvage enzyme, adenosine deaminase. The pathophysiology involves lymphocytes of both thymic and bone-marrow origin (T and B lymphocytes), as well as 'self-destruction' of differentiated cells following antigen stimulation. The precise cause of cell death is not yet known, but may involve accumulation in lymphoid tissues of adenosine, deoxyadenosine and dATP, accompanied by ATP depletion. The finding that deficiency of the next enzyme in the purine salvage pathway, nucleoside phosphorylase, is also associated with an immune-deficiency disorder suggests that integrity of the purine salvage pathway is critical for normal differentiation and function of immunocompetent cells in man. |
| Treatment of SCIDS patients has focused on two regimens. First, allogeneic bone marrow transplantation is generally successful. However the severe complications of graft-versus-host disease (GVHD) caused by non-identical donors coupled with only partial restoration of function in treated patients has led to the development of gene replacement therapies. Trials during the 1990s on correction of adenosine deaminase deficiencies in T lymphocytes or in stem cells with retroviral mediated gene transfer met with limited success. However, more recent results using improved techniques coupled with a better understanding of stem cell biology have resulted in successful gene transfer to patients with results comparable or better than can be achieved by bone marrow transplant. |
| UTP is synthesized in two enzymatic phosphorylation steps by the actions of UMP kinase and nucleotide diphosphokinase.
UMP kinase can convert both UMP and CMP into UDP and CDP respectively. Again, as with the purines, nucleotide diphosphokinase converts the diphosphates into triphosphates. CTP synthetase converts UTP into CTP by amination of UTP. The nitrogen group is donated from glutamine in mammals. In bacteria, the nitrogen comes directly from ammonia (Fig. 29.6).
|
|
