Alternative titles; symbols
HGNC Approved Gene Symbol: AMD1
Cytogenetic location: 6q21 Genomic coordinates (GRCh38): 6:110,814,617-110,895,713 (from NCBI)
S-adenosylmethionine (AdoMet) decarboxylase (EC 4.1.1.50) is a key enzyme in polyamine biosynthesis, and the product of the catalytic reaction, decarboxylated AdoMet, serves as an aminopropyl donor in the biosynthesis of spermidine and spermine (summary by Maric et al., 1992).
Pajunen et al. (1988) cloned cDNAs encoding S-adenosylmethionine decarboxylase from rat prostate and human fibroblast cDNA libraries. The deduced amino acid sequences indicated that the human proenzyme for this protein contains 334 amino acids and has a molecular mass of 38.3 kD, whereas the rat proenzyme contains 333 amino acids. The human and rat proteins have only 11 amino acid differences. In vitro transcription/translation experiments showed that the proenzyme is converted to 2 polypeptides (about 32 and 6 kD) in a processing reaction which generates the prosthetic pyruvate group and that the final enzyme contains both polypeptides. Two mRNA transcripts (2.1 and about 3.4-3.6 kb) were expressed in rat and human tissues.
A rat cDNA clone for AdoMetDC was used by Radford et al. (1987, 1989) in mouse-human somatic cell hybrid experiments to map the AMD gene to chromosomes 6 and X. They demonstrated that the gene on chromosome 6, symbolized AMD1, is not amplified in colon neoplasia. The sequence on X, symbolized AMD2, was localized to Xq22-q28 and may represent a pseudogene. That AMD2 is indeed a pseudogene was indicated by the findings of Maric et al. (1992) that the X-chromosome gene lacks introns which are present in the chromosome 6 gene.
By fluorescence in situ hybridization, Maric et al. (1995) mapped AMD1 to 6q21-q22 and the AMD2 pseudogene to Xq28.
Maric et al. (1992) determined that the AMD1 gene encompasses at least 22 kb and contains 9 exons, in contrast to the corresponding rat gene, which has 8 exons.
Maric et al. (1995) characterized the AMD pseudogene on the X chromosome. It lacks all the introns present in AMD1 and has numerous mutations in the protein-coding region.
Pulkka et al. (1993) characterized 2 AMD genes in the rat and localized both to rat chromosome 20 by mouse-rat somatic cell hybrids. They showed a high degree of conservation of sequence and structural organization in the coding portions but the 5-prime flanking regions were totally different.
To identify tumor suppressor genes in lymphoma (605027), Scuoppo et al. (2012) screened a short hairpin RNA library targeting genes deleted in human lymphomas and functionally confirmed those in a mouse lymphoma model. Of the 9 tumor suppressors identified, 8 corresponded to genes occurring in 3 physically linked 'clusters,' suggesting that the common occurrence of large chromosomal deletions in human tumors reflects selective pressure to attenuate multiple genes. Among the newly identified tumor suppressors were adenosylmethionine decarboxylase-1 and eukaryotic translation initiation factor 5A (eIF5A; 600187), 2 genes associated with hypusine, a unique amino acid produced as a product of polyamine metabolism through a highly conserved pathway. Through a secondary screen surveying the impact of all polyamine enzymes on tumorigenesis, Scuoppo et al. (2012) established the polyamine-hypusine axis as a new tumor suppressor network regulating apoptosis. Unexpectedly, heterozygous deletions encompassing AMD1 and eIF5A often occur together in human lymphomas, and cosuppression of both genes promotes lymphomagenesis in mice. Thus, Scuoppo et al. (2012) concluded that some tumor suppressor functions can be disabled through a 2-step process targeting different genes acting in the same pathway.
Zabala-Letona et al. (2017) used integrative metabolomics in a mouse model and human biopsies of prostate cancer (see 176807) to identify alterations in tumors affecting the production of decarboxylated S-adenosylmethionine and polyamine synthesis. Mechanistically, this metabolic rewiring stems from mTORC1 (see 601231)-dependent regulation of AMD1 stability. This novel molecular regulation was validated in mouse and human cancer specimens. AMD1 was upregulated in human prostate cancer with activated mTORC1. Conversely, samples from a clinical trial with the mTORC1 inhibitor everolimus exhibited a predominant decrease in AMD1 immunoreactivity that was associated with a decrease in proliferation, in line with the requirement of decarboxylated S-adenosylmethionine production for oncogenicity.
Yordanova et al. (2018) reported a novel mechanism that limits the number of complete protein molecules that can be synthesized from a single mRNA molecule of the human AMD1 gene, encoding adenosylmethionine decarboxylase-1 (AdoMetDC). A small proportion of ribosomes translating AMD1 mRNA stochastically read through the stop codon of the main coding region. These read-through ribosomes then stall close to the next in-frame stop codon, eventually forming a ribosome queue, the length of which is proportional to the number of AdoMetDC molecules that were synthesized from the same AMD1 mRNA. Once the entire spacer region between the 2 stop codons is filled with queueing ribosomes, the queue impinges upon the main AMD1 coding region, halting its translation. Phylogenetic analysis suggested that this mechanism is highly conserved in vertebrates and existed in their common ancestor. Yordanova et al. (2018) proposed that this mechanism is used to count and limit the number of protein molecules that can be synthesized from a single mRNA template. They hypothesized that it could serve to safeguard from dysregulated translation that may occur owing to errors in transcription or mRNA damage.
Maric, S. C., Crozat, A., Janne, O. A. Structure and organization of the human S-adenosylmethionine decarboxylase gene. J. Biol. Chem. 267: 18915-18923, 1992. [PubMed: 1527020]
Maric, S. C., Crozat, A., Louhimo, J., Knuutila, S., Janne, O. A. The human S-adenosylmethionine decarboxylase gene: nucleotide sequence of a pseudogene and chromosomal localization of the active gene (AMD1) and the pseudogene (AMD2). Cytogenet. Cell Genet. 70: 195-199, 1995. [PubMed: 7789170] [Full Text: https://doi.org/10.1159/000134032]
Pajunen, A., Crozat, A., Janne, O. A., Ihalainen, R., Laitinen, P. H., Stanley, B., Madhubala, R., Pegg, A. E. Structure and regulation of mammalian S-adenosylmethionine decarboxylase. J. Biol. Chem. 263: 17040-17049, 1988. [PubMed: 2460457]
Pulkka, A., Ihalainen, R., Suorsa, A., Riviere, M., Szpirer, J., Pajunen, A. Structures and chromosomal localizations of two rat genes encoding S-adenosylmethionine decarboxylase. Genomics 16: 342-349, 1993. [PubMed: 8314573] [Full Text: https://doi.org/10.1006/geno.1993.1195]
Radford, D. M., Eddy, R., Haley, L., Henry, W. M., Pegg, A. E., Pajunen, A., Shows, T. B. Gene sequences coding for S-adenosylmethionine decarboxylase are present on human chromosome 6 and the X and are not amplified in colon neoplasia. Cytogenet. Cell Genet. 49: 285-288, 1989.
Radford, D. M., Nakai, H., Pegg, A. E., Shows, T. B. Mapping genes for rate-limiting enzymes in polyamine biosynthesis. (Abstract) Am. J. Hum. Genet. 41: A35 only, 1987.
Scuoppo, C., Miething, C., Lindqvist, L., Reyes, J., Ruse, C., Appelmann, I., Yoon, S., Krasnitz, A., Teruya-Feldstein, J., Pappin, D., Pelletier, J., Lowe, S. W. A tumour suppressor network relying on the polyamine-hypusine axis. Nature 487: 244-248, 2012. [PubMed: 22722845] [Full Text: https://doi.org/10.1038/nature11126]
Yordanova, M. M., Loughran, G., Zhdanov, A. V., Mariotti, M., Kiniry, S. J., O'Connor, P. B. F., Andreev, D. E., Tzani, I., Saffert, P., Michel, A. M., Gladyshev, V. N., Papkovsky, D. B., Atkins, J. F., Baranov, P. V. AMD1 mRNA employs ribosome stalling as a mechanism for molecular memory formation. Nature 553: 356-360, 2018. [PubMed: 29310120] [Full Text: https://doi.org/10.1038/nature25174]
Zabala-Letona, A., Arruabarrena-Aristorena, A., Martin-Martin, N., Fernandez-Ruiz, S., Sutherland, J. D., Clasquin, M., Tomas-Cortazar, J., Jimenez, J., Torres, I., Quang, P., Ximenez-Embun, P., Bago, R., and 52 others. mTORC1-dependent AMD1 regulation sustains polyamine metabolism in prostate cancer. Nature 547: 109-113, 2017. Note: Erratum: Nature 554: 554 only, 2018. [PubMed: 28658205] [Full Text: https://doi.org/10.1038/nature22964]