Human Biochemistry, Volume 1 - Murray R. 1993

Protein and Amino Acid Metabolism
Conversion of Amino Acids into Specialized Products
Ornithine

In addition to its role in urea Biosynthesis (see Chapter 30), ornithine (along with Methionine) serves as a precursor for the Polyamines spermine and spermidine (Fig. 32.5), which are widely distributed in mammals and Bacteria. A healthy human body synthesizes approximately 0.5 mmol of spermine per day. Pharmacological doses of polyamines induce hypothermia and a drop in Blood pressure.

Spermidine and spermine are involved in various physiological processes, all of which share a common link to Cell proliferation and growth. They act as growth factors for mammalian and bacterial cell cultures and play a key role in stabilizing intact Cells, subcellular Organelles, and membranes. Because polyamine molecules carry a high positive charge, they readily associate with polyanions such as DNA and RNA, participating in fundamental processes such as The stimulation of DNA and RNA biosynthesis, DNA stabilization, and DNA packaging in Bacteriophages. Polyamines also influence Protein Synthesis AND act as inhibitors of several Enzymes, including protein Kinases.

Although the exact mechanism of polyamine action on specific metabolic processes remains elusive, their vital role in mammalian METABOLISM is convincingly demonstrated by experiments of the following type. The initial reaction in polyamine biosynthesis is catalyzed by ornithine decarboxylase (Fig. 32.6). The addition of ornithine decarboxylase inhibitors (e.g., α-methylornithine or difluoromethylornithine) to mammalian cell cultures triggers an upregulation of ornithine decarboxylase synthesis. This highlights the critical physiological importance of this enzyme, whose only known function is polyamine biosynthesis.

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Fig. 32.5. Structures of naturally occurring polyamines. Note that spermidine and spermine are polymers of diaminopropane (A) and diaminobutane (B). Diaminopentane (cadaverine) is also present in mammalian Tissues.

Polyamine biosynthesis

Fig. 32.6 illustrates the metabolic pathway of polyamine biosynthesis in mammalian tissues. Note that the putrescine moiety of spermidine and spermine is derived from L-ornithine (an intermediate of The Urea Cycle, see Ch. 30), whereas the diaminopropane moiety originates from L-methionine (via The intermediate formation of S-adenosylmethionine). Ornithine decarboxylase and S-adenosylmethionine decarboxylase are inducible enzymes with short half-lives. In contrast, spermine and spermidine synthases are non-inducible and relatively stable.

Among the enzymes involved in mammalian polyamine biosynthesis, ornithine decarboxylase and S-adenosylmethionine decarboxylase are of particular interest regarding their regulation and potential Applications in targeted Chemotherapy. The half-life of ornithine decarboxylase (approximately 10 min) is shorter than that of any other known mammalian enzyme; its activity changes rapidly and dramatically in response to various stimuli. The addition of Growth Hormone, corticosteroids, testosterone, or epidermal growth factor to mammalian cell cultures rapidly increases ornithine decarboxylase activity by 10- to 200-fold. Supplementing cell cultures with polyamines induces the synthesis of a protein antizyme, which binds to ornithine decarboxylase and inhibits its activity. Thus, ornithine decarboxylase activity is regulated through Protein-Structure/156.html">Protein Interactions, akin to The regulation of Trypsin activity by protein inhibitors. Difluoromethylornithine can be regarded as a "suicide inhibitor" of ornithine decarboxylase—that is, a compound converted into an active inhibitor by the action of the enzyme itself. It is employed to isolate mutant cell lines characterized by ornithine decarboxylase overproduction, as well as an inhibitor of cell Replication acting as an enzyme-targeted chemotherapeutic agent.

S-Adenosylmethionine decarboxylase is the only known eukaryotic enzyme containing Pyruvate as a covalently bound cofactor (most Decarboxylases rely on Pyridoxal phosphate, which is absent in S-adenosylmethionine decarboxylase). S-Adenosylmethionine decarboxylase has a relatively short half-life (1–2 h) and responds to cell growth stimuli similarly to ornithine decarboxylase, albeit somewhat more slowly and to a lesser extent. The activity of S-adenosylmethionine decarboxylase (Fig. 32.6) is inhibited by decarboxylated S-adenosylmethionine and stimulated by putrescine.

Polyamine Catabolism

Fig. 32.7 outlines The pathway of polyamine catabolism in mammalian tissues. The enzyme polyamine oxidase, located in Liver Peroxisomes, oxidizes spermine to spermidine, and subsequently spermidine to putrescine. Both diaminopropane moieties are converted into ß-aminopropionaldehyde. A fraction of the resulting putrescine is oxidized to NH⁺₄ and CO₂ through a mechanism that remains to be fully elucidated. The bulk of putrescine and spermidine is excreted in the urine as conjugates, predominantly in the form of acetyl derivatives.