Spermidine synthase

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spermidine synthase
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Spermidine synthase tetramer, Bacillus subtilis
Identifiers
SymbolSRM
Alt. symbolsSRML1
NCBI gene 6723
HGNC 11296
OMIM 182891
RefSeq NM_003132
UniProt P19623
Other data
EC number 2.5.1.16
Locus Chr. 1 p36-p22
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Structures Swiss-model
Domains InterPro

Spermidine synthase is an enzyme (EC 2.5.1.16) that catalyzes the transfer of the propylamine group from S-adenosylmethioninamine to putrescine in the biosynthesis of spermidine. The systematic name is S-adenosyl 3-(methylthio)propylamine:putrescine 3-aminopropyltransferase and it belongs to the group of aminopropyl transferases. It does not need any cofactors. Most spermidine synthases exist in solution as dimers. [1]

Contents

Specificity

With exception of the spermidine synthases from Thermotoga maritimum and from Escherichia coli, which accept different kinds of polyamines, all enzymes are highly specific for putrescine. [2] No known spermidine synthase can use S-adenosyl methionine. This is prevented by a conserved aspartatyl residue in the active site, which is thought to repel the carboxyl moiety of S-adenosyl methionine. [3] The putrescine-N-methyl transferase whose substrates are putrescine and S-adenosyl methionine, and which is evolutionary related to the spermidine synthases, lacks this aspartyl residue. [4] It is even possible to convert the spermidine synthase by some mutations to a functional putrescine-N-methyltransferase. [5]

Mechanism

It is assumed that the synthesis of spermidine follows the Sn2 mechanism. [6] There is some uncertainty if the reaction occurs via a ping-pong or via a ternary-complex mechanism. Some kinetic data, but not all, suggest a ping-pong mechanism, [7] while the investigation of the stereochemical path of the reaction argues for a ternary-complex mechanism. [8] Prior to the nucleophilic attack of the putrescine onto the S-adenosylmethioninamine the putrescine has to be deprotonated rendering the nitrogen nucleophilic since the putrescine is protonated at physiological pH and is therefore inactive.

Inhibitors

The spermidine synthase can be inhibited by a wide variety of analogues of putrescine, S-adenosyl methioninamine and transition state analogues as Adodato (for further information see here)

See also

Related Research Articles

<i>S</i>-Adenosyl methionine Chemical compound found in all domains of life with largely unexplored effects

S-Adenosyl methionine (SAM), also known under the commercial names of SAMe, SAM-e, or AdoMet, is a common cosubstrate involved in methyl group transfers, transsulfuration, and aminopropylation. Although these anabolic reactions occur throughout the body, most SAM is produced and consumed in the liver. More than 40 methyl transfers from SAM are known, to various substrates such as nucleic acids, proteins, lipids and secondary metabolites. It is made from adenosine triphosphate (ATP) and methionine by methionine adenosyltransferase. SAM was first discovered by Giulio Cantoni in 1952.

Spermine is a polyamine involved in cellular metabolism that is found in all eukaryotic cells. The precursor for synthesis of spermine is the amino acid ornithine. It is an essential growth factor in some bacteria as well. It is found as a polycation at physiological pH. Spermine is associated with nucleic acids and is thought to stabilize helical structure, particularly in viruses. It functions as an intracellular free radical scavenger to protect DNA from free radical attack. Spermine is the chemical primarily responsible for the characteristic odor of semen.

<span class="mw-page-title-main">Methyltransferase</span> Group of methylating enzymes

Methyltransferases are a large group of enzymes that all methylate their substrates but can be split into several subclasses based on their structural features. The most common class of methyltransferases is class I, all of which contain a Rossmann fold for binding S-Adenosyl methionine (SAM). Class II methyltransferases contain a SET domain, which are exemplified by SET domain histone methyltransferases, and class III methyltransferases, which are membrane associated. Methyltransferases can also be grouped as different types utilizing different substrates in methyl transfer reactions. These types include protein methyltransferases, DNA/RNA methyltransferases, natural product methyltransferases, and non-SAM dependent methyltransferases. SAM is the classical methyl donor for methyltransferases, however, examples of other methyl donors are seen in nature. The general mechanism for methyl transfer is a SN2-like nucleophilic attack where the methionine sulfur serves as the leaving group and the methyl group attached to it acts as the electrophile that transfers the methyl group to the enzyme substrate. SAM is converted to S-Adenosyl homocysteine (SAH) during this process. The breaking of the SAM-methyl bond and the formation of the substrate-methyl bond happen nearly simultaneously. These enzymatic reactions are found in many pathways and are implicated in genetic diseases, cancer, and metabolic diseases. Another type of methyl transfer is the radical S-Adenosyl methionine (SAM) which is the methylation of unactivated carbon atoms in primary metabolites, proteins, lipids, and RNA.

<span class="mw-page-title-main">Adenosylmethionine decarboxylase</span> Class of enzymes

The enzyme adenosylmethionine decarboxylase catalyzes the conversion of S-adenosyl methionine to S-adenosylmethioninamine. Polyamines such as spermidine and spermine are essential for cellular growth under most conditions, being implicated in many cellular processes including DNA, RNA and protein synthesis. S-adenosylmethionine decarboxylase (AdoMetDC) plays an essential regulatory role in the polyamine biosynthetic pathway by generating the n-propylamine residue required for the synthesis of spermidine and spermine from putrescein. Unlike many amino acid decarboxylases AdoMetDC uses a covalently bound pyruvate residue as a cofactor rather than the more common pyridoxal 5'-phosphate. These proteins can be divided into two main groups which show little sequence similarity either to each other, or to other pyruvoyl-dependent amino acid decarboxylases: class I enzymes found in bacteria and archaea, and class II enzymes found in eukaryotes. In both groups the active enzyme is generated by the post-translational autocatalytic cleavage of a precursor protein. This cleavage generates the pyruvate precursor from an internal serine residue and results in the formation of two non-identical subunits termed alpha and beta which form the active enzyme.

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References

  1. Ikeguchi Y, Bewley MC, Pegg AE (January 2006). "Aminopropyltransferases: function, structure and genetics". Journal of Biochemistry. 139 (1): 1–9. doi:10.1093/jb/mvj019. PMID   16428313.
  2. Wu H, Min J, Ikeguchi Y, Zeng H, Dong A, Loppnau P, Pegg AE, Plotnikov AN (July 2007). "Structure and mechanism of spermidine synthases". Biochemistry. 46 (28): 8331–9. doi:10.1021/bi602498k. PMID   17585781.
  3. Korolev S, Ikeguchi Y, Skarina T, Beasley S, Arrowsmith C, Edwards A, Joachimiak A, Pegg AE, Savchenko A (January 2002). "The crystal structure of spermidine synthase with a multisubstrate adduct inhibitor". Nature Structural Biology. 9 (1): 27–31. doi:10.1038/nsb737. PMC   2792006 . PMID   11731804.
  4. Biastoff S, Brandt W, Dräger B (2009-10-01). "Putrescine N-methyltransferase--the start for alkaloids". Phytochemistry. Evolution of Metabolic Diversity. 70 (15–16): 1708–18. Bibcode:2009PChem..70.1708B. doi:10.1016/j.phytochem.2009.06.012. PMID   19651420.
  5. Junker A, Fischer J, Sichhart Y, Brandt W, Dräger B (2013-01-01). "Evolution of the key alkaloid enzyme putrescine N-methyltransferase from spermidine synthase". Frontiers in Plant Science. 4: 260. doi: 10.3389/fpls.2013.00260 . PMC   3725402 . PMID   23908659.
  6. Golding B, Nassereddin lK, Billington D. "The Biosynthesis of Spermidine. Part I : Biosynthesis of Spermidine from L-[3,4-13C2] Methionine and L-[2,3,3-2H3] Methionine". J. Chem. Soc. Perkin Trans.
  7. Yoon SO, Lee YS, Lee SH, Cho YD (June 2000). "Polyamine synthesis in plants: isolation and characterization of spermidine synthase from soybean (Glycine max) axes". Biochimica et Biophysica Acta (BBA) - General Subjects. 1475 (1): 17–26. doi:10.1016/s0304-4165(00)00039-8. PMID   10806333.
  8. Golding B, Nassereddin I (1985). "The Biosynthesis of Spermidine. Part 3: The Stereochemistry of the Formationof the N-CH2, Group in the Biosynthesis of Spermidine". J. Chem. Soc. Perkin Trans.: 2017. doi:10.1039/P19850002017.