Mutational biosynthesis

ANTIPROTOZOAL EFFECTS Miltefosine is the first orally available therapy for leishmaniasis. It is safe and effective treatment for visceral leishmaniasis and has also shown >95% efficacy against cutaneous leishmaniasis. In Leishmania, the drug may alter ether-lipid metabohsm, ceU signaling, or glycosylphosphatidylinosital anchor biosynthesis. Mutations in a P-type ATPase of the aminophospholipid translocase subfamily apparently decrease drug uptake and thereby confer resistance. 

Cleaver JE (1984) Differential toxicity of 3-aminobenzamide to wild-type and 6-thioguanine-resistant Chinese hamster cells by interference with pathways of purine biosynthesis. Mutat Res 131 123-127... 

Many kinds of amino acids (eg, L-lysine, L-omithine, t-phenylalanine, L-threonine, L-tyrosine, L-valine) are accumulated by auxotrophic mutant strains (which are altered to require some growth factors such as vitamins and amino acids) (Table 6, Primary mutation) (22). In these mutants, the formation of regulatory effector(s) on the amino acid biosynthesis is genetically blocked and the concentration of the effector(s) is kept low enough to release the regulation and iaduce the overproduction of the corresponding amino acid and its accumulation outside the cells (22). 

CYP27A1 catalyzes the side chain oxidation (27-hydroxylation) in bile acid biosynthesis. Because bile acid synthesis is the only elimination pathway for cholesterol, mutations in the CYP27A1 gene lead to abnormal deposition of cholesterol and cholestanol in various tissues. This sterol storage disorder is known as cerebrotendinous xanthomatosis. CYP27B1 is the 1-alpha hydroxylase of vitamin D3 that converts it to the active vitamin form. The function of CYP27C1 is not yet known. 

Table 48-4. Diseases caused by mutations in coiiagen genes or by deficiencies in the activities of posttranslational enzymes involved in the biosynthesis of collagen. ...

Although uptake and accumulation of most amino acids from the external medium seems to be irreversible, amino acids are excreted into the medium whenever they are overproduced above a given threshold by yeast cells [6], This can occur under a number of specific conditions, namely in mutants with impaired regulation of amino acid biosynthesis, or in the presence of mutations preventing substrate catabolism, or when growth occurs in the presence of metabolic intermediates. It can even occur when growth is arrested under conditions where amino acid synthesis can continue. 

Mutations in the gene for adenylosuccinate lyase (ASL), inherited as an autosomal recessive disorder in purine metabolism, are associated with severe mental retardation and autistic behavior, but apparently not self-mutilation [10, 11]. This enzyme catalyzes two distinct reactions in the de novo biosynthesis of purines the cleavages of adenylosuccinate (S-Ado) and succinylaminoimidazole carboxamide ribotide (SAICAR), both of which accumulate in plasma, urine and cerebrospinal fluid of affected individuals [12]. Measurements of these metabolites in urine... 

Inhibition of the lipid modification cascade provides an alternative way to block aberrant signaling pathways and that opportunity can be exploited in anticancer therapy. As part of the growth factor, signaling of the false activation is transmitted by the mutated ras gene encoded proteins (Ras) and ultimately leads to uncontrolled cell growth. These typical GTP binding proteins are also subject to membrane anchoring and the biosynthesis of those Ras proteins can be blocked at the posttranslational prenylation step. 

Genetic analysis indicates that two of the 10 sad mutants of A. strigosa that we isolated represent different mutant alleles at the Sadi locus.6 These mutants accumulate radiolabelled 2,3-oxidosqualene but not p-amyrin when the roots are fed with 14C-labelled precursor mevalonic acid, suggesting that the triterpenoid pathway is blocked between 2,3-oxidosqualene and P-amyrin.34 The roots of these mutants also lack detectable P-amyrin synthase activity, but, like the wild type and the other mutants, are unimpaired in cycloartenol synthase (CS) activity and sterol biosynthesis.34 The transcript levels for AsbASl are substantially reduced in roots of sadl mutants, while AsCSl transcript levels are unaffected,35 suggesting that the sadl mutants are either mutated in the AsbASl gene itself or in a gene involved in its regulation. 

A MUTATIONAL APPROACH TO DISSECTION OF FLAVONOID BIOSYNTHESIS IN ARABIDOPSIS... 

BURBULIS, I.E., IACOBUCCI, M., SHIRLEY, B.W., A null mutation in the first enzyme of flavonoid biosynthesis does not affect male fertility in Arabidopsis, Plant Cell, 1996, 8,1013-1025. 

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