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Review
. 2022 Apr 12;12(4):344.
doi: 10.3390/metabo12040344.

Role of Polyamines and Hypusine in β Cells and Diabetes Pathogenesis

Abhishek Kulkarni  1 , Cara M Anderson  1 , Raghavendra G Mirmira  1 , Sarah A Tersey  1
Affiliations
Review

Role of Polyamines and Hypusine in β Cells and Diabetes Pathogenesis

Abhishek Kulkarni et al. Metabolites. .

Abstract

The polyamines-putrescine, spermidine, and spermine-are polycationic, low molecular weight amines with cellular functions primarily related to mRNA translation and cell proliferation. Polyamines partly exert their effects via the hypusine pathway, wherein the polyamine spermidine provides the aminobutyl moiety to allow posttranslational modification of the translation factor eIF5A with the rare amino acid hypusine (hydroxy putrescine lysine). The "hypusinated" eIF5A (eIF5Ahyp) is considered to be the active form of the translation factor necessary for the translation of mRNAs associated with stress and inflammation. Recently, it has been demonstrated that activity of the polyamines-hypusine circuit in insulin-producing islet β cells contributes to diabetes pathogenesis under conditions of inflammation. Elevated levels of polyamines are reported in both exocrine and endocrine cells of the pancreas, which may contribute to endoplasmic reticulum stress, oxidative stress, inflammatory response, and autophagy. In this review, we have summarized the existing research on polyamine-hypusine metabolism in the context of β-cell function and diabetes pathogenesis.

Keywords: diabetes; eIF5A; hypusine; polyamines; putrescine; spermidine; spermine; β cells.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Polyamines Biosynthesis and Catabolic Pathway. Polyamine biosynthesis begins with arginine, where arginase (ARG) converts arginine to ornithine. Next, ornithine decarboxylase (ODC) converts ornithine to putrescine. S-adenosylmethionine decarboxylase (SamDC) then catalyzes the decarboxylation of S-adenosylmethionine. Next, spermidine synthase (SpdS) then transfers the aminopropyl moiety from the decarboxylated S-adenosylmethionine to putrescine, converting it into spermidine. Finally, spermine synthase (SpmS) catalyzes a similar aminopropyl transfer activity from the decarboxylated S-adenosylmethionine to convert spermidine to spermine. Polyamine catabolism is catalyzed by spermine/spermidine N1-acetyltransferase (SSAT) and N1-acetylpolyamine oxidase (PAO). SSAT can acetylate spermine and spermidine to N-acetylspermine and N-acetylspermidine, respectively. These acetylated products can be cleaved by PAO into spermidine and putrescine along with a generation of H2O2. Spermine can also be oxidized to spermidine by the enzyme spermine oxidase (SMO). For studying the polyamines pathway, two commonly used drugs include difluoromethylornithine (DFMO) which irreversibly inhibits ODC, and N1,N11-diethylnorspermine (DENspm) which activates SSAT.
Figure 2
Figure 2
Hypusine Pathway. Spermidine is used as a substrate to form deoxyhypusine by the rate-limiting enzyme deoxyhypusine synthase (DHPS), which then transfers deoxyhypusine to eIF5A. Deoxyhypusine is then converted to hypusine by deoxyhypusine hydroxylase (DOHH), resulting in hypusinated eIF5A.
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