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Updated: May 5, 2026

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Transition metal activation reframes SAMHD1 regulation.

Logan A Calderone1, Anthony Gizzi2, Soumika Pinninti1

  • 1Department of Biochemistry, Brandeis University, Waltham, Massachusetts 02453, United States.

Biorxiv : the Preprint Server for Biology
|May 4, 2026
PubMed
Summary
This summary is machine-generated.

Iron is crucial for SAMHD1 enzyme function, acting as a key structural and regulatory cofactor. This research reveals how iron and other transition metals enable SAMHD1

Keywords:
BiochemistryBiological SciencesEPRallosteric activationdeoxytriphosphohydrolaseironmanganese

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Area of Science:

  • Biochemistry
  • Enzymology
  • Structural Biology

Background:

  • SAMHD1 is a human enzyme critical for regulating nucleotide pools and restricting HIV.
  • Its role in viral restriction, chemotherapy resistance, and Aicardi-Goutières syndrome is known, but its metal cofactor requirements are unclear.
  • Previous studies focused on substrate promiscuity, overlooking the mechanistic roles of metal cofactors.

Purpose of the Study:

  • To elucidate the molecular mechanisms of metal-dependent activation and catalysis in SAMHD1.
  • To identify the specific metal cofactors and their roles in SAMHD1's structure and function.
  • To understand how transition metals influence SAMHD1's activity in diverse cellular environments.

Main Methods:

  • Elemental analysis
  • Spectroscopy
  • Protein cross-linking
  • Enzyme kinetics
  • Analysis of metal cofactor requirements

Main Results:

  • Transition metals, particularly iron, are essential for SAMHD1 function, not magnesium.
  • Iron plays a central structural and regulatory role, organizing the dinuclear active site.
  • SAMHD1 forms diiron and heterodinuclear iron-containing cofactors that support catalysis.
  • The enzyme exhibits cofactor promiscuity at the second metal site, accommodating various divalent metals.
  • Manganese can substitute for iron but alters metal binding equilibria.

Conclusions:

  • Iron is a core structural and functional determinant of SAMHD1 catalysis.
  • SAMHD1 is a transition-metal-dependent hydrolase with iron playing a pivotal role.
  • The enzyme's flexibility in metal cofactor utilization allows it to adapt to varying cellular metal conditions and redox environments.
  • These findings redefine the understanding of SAMHD1's enzymatic activity and its regulation.