Polyamine catabolism and disease

Abstract

In addition to polyamine homoeostasis, it has become increasingly clear that polyamine catabolism can play a dominant role in drug response, apoptosis and the response to stressful stimuli, and contribute to the aetiology of several pathological states, including cancer. The highly inducible enzymes SSAT (spermidine/spermine N1-acetyltransferase) and SMO (spermine oxidase) and the generally constitutively expressed APAO (N1-acetylpolyamine oxidase) appear to play critical roles in many normal and disease processes. The dysregulation of polyamine catabolism frequently accompanies several disease states and suggests that such dysregulation may both provide useful insight into disease mechanism and provide unique druggable targets that can be exploited for therapeutic benefit. Each of these enzymes has the potential to alter polyamine homoeostasis in response to multiple cell signals and the two oxidases produce the reactive oxygen species H2O2 and aldehydes, each with the potential to produce pathological states. The activity of SSAT provides substrates for APAO or substrates for the polyamine exporter, thus reducing the intracellular polyamine concentration, the net effect of which depends on the magnitude and rate of any increase in SSAT. SSAT may also influence cellular metabolism via interaction with other proteins and by perturbing the content of acetyl-CoA and ATP. The goal of the present review is to cover those aspects of polyamine catabolism that have an impact on disease aetiology or treatment and to provide a solid background in this ever more exciting aspect of polyamine biology.

Figure 1

The polyamine metabolic pathway. ODC, ornithine decarboxylase; AdoMet, S-adenosylmethionine; AdoMetDC, S-adenosylmethionine decarboxylase, this enzyme provides the aminopropyl group for the synthesis of spermidine and spermine from putrescine and spermidine, respectively; MTA, methylthioadeonsine; SMO, spermine oxidase is an inducible enzyme that produces the reactive oxygen species, H₂O₂ and the aldehyde, 3-aminopropanal; SSAT, spermidine/spermine N¹-acetyltransferase produces the acetylated polyamines that can be oxidized by APAO or excreted from the cell; APAO, N¹-acetylpolyamine oxidase is a peroxisomal enzyme that oxidizes N1-acetylated polyamines producing 3-acetoaminopropanal and H₂O₂; DFMO, 2-difluoromethylornithine (an inhibitor of ODC); MDL 72527, N¹,N⁴-bis(buta-2,3-dienyl)butanediamine (an inhibitor of both APAO and SMO).

Figure 2

Reactions catalyzed by SSAT and APAO. Physiological substrates for SSAT are spermidine, spermine and N¹-acetylspermine. Physiological substrates for APAO are N¹-acetylspermidine, N¹-acetylspermine and N¹,N¹²-acetylspermine.

Figure 3

Structure of SSAT. (A) Molecular surface of SSAT dimer colored according to element (nitrogen, blue; oxygen, red; carbon, grey; sulfur, yellow) with acetyl CoAs shown in green. (B) BENSpm bound to SSAT. Residues from one subunit are shown in green and from the other in purple. (C) Reaction mechanism showing role of Tyr140 and Glu92.

Figure 4

Futile cycle formed by SSAT. Elevations in SSAT aided by excretion of the acetylated products and putrescine formed by APAO cause a decrease in polyamine content. If this is compensated for by an increase in polyamine biosynthetic enzymes, a futile cycle, which depletes ATP and acetyl CoA, is created.

Figure 5

Potential damage resulting from polyamine oxidation. Intracellular polyamines can be oxidized by both SMO and APAO. Here the potential damage resulting from spermine oxidation by SMO is illustrated. The red lightening bolts represent potentially damaging insults from reactive aldehydes and the blue lightening bolts represent potentially damaging reactive oxygen species (1) The reactive aldehyde, 3-aminopropanal, can damage () RNA (4), DNA (5), proteins (6), and membranes (7). Similarly, the readily diffusible H₂O₂ (2) can damage () RNA, DNA, membranes, and proteins, once converted to the highly reactive hydroxyl radical (3) through Fenton or Fenton-like catalysis. If oxidative damage to cells is severe enough, apoptotic cell death may ensue (8). Heritable damage to DNA may result in transformation, carcinogenesis (9) and metastatic disease. Although unexplored, H₂O₂ produced by polyamine catabolism may play a role as a signaling molecule (10).

Figure 6

Representative SMO immunohistochemical staining observed in prostate epithelial tissue microarrays. (A) normal prostate tissue, (B) benign prostate tissue from prostate cancer patient, (C) prostatic intraepithelial neoplasia, and (D) prostate adenocarcinoma.