Cofactors are essentially helper molecules that allow biochemical reactions to occur. Some cofactors are inorganic metal ions such as iron and magnesium. Organic (carbon-containing) cofactors are sometimes classified more specifically as “coenzymes”, as they primarily assist the action of enzymes, but these words can generally be used interchangeably. All of the water-soluble vitamins (Bs and C), and two fat-soluble vitamins (A and K) fall into this category of coenzymes/cofactors [1].

How do cofactors help?

Vitamin cofactors are involved in a multitude of biochemical reactions involving energy metabolism. They are also necessary for processes involved in proper vision, blood coagulation, hormone production, and the integrity of collagen, a protein found in bones, skin, cartilage, and other structural tissues [1]. 

Vitamin A, specifically in its aldehyde form, retinal, acts as a cofactor in the retina for the function of dim-light vision in rods, and bright-light and color vision in cones [1].

Vitamin K acts as a coenzyme for γ-carboxylases, which are the enzymes that transfer carbon dioxide groups for calcium-binding. Vitamin K deficiency would, therefore, slow the processes that lead to bone remodeling and blood clotting [1].

The active form of thiamine (vitamin B-1) is a cofactor in the breakdown of carbohydrates. 

Some cofactors function by ferrying electrons or negative charges to enhance a reaction. Vitamins B-2, B-3, and C are all precursors of electron-carrying coenzymes. Vitamin C (ascorbic acid) is a cofactor for the hydroxylase enzymes. These are the enzymes that support the structural integrity of collagen, the hydroxylation of cholesterol to form bile acids, and the synthesis of norepinephrine (noradrenaline) from the amino acid tyrosine [1]. Three activated forms of riboflavin (vitamin B-2) serve as hydrogen carriers to assist in the Kreb’s/citric acid cycle that produces cellular energy. The vitamin cofactor forms of niacin (B-3) are involved in the catabolism of fat, carbohydrates, and amino acids, and in the enzymes involved in the synthesis of fats, steroids, and other vital metabolites. 

B-5 (Pantothenic acid) is a component of coenzyme A. Coenzyme A is necessary for the metabolism of carbohydrates, amino acids, fatty acids, and other biomolecules as well as the synthesis of fatty acids. Vitamin B-6 has two coenzyme forms that serve as cofactors in over 120 enzyme reactions (too many to list here). Vitamin B-12 serves as an important cofactor in methylation: converting homocysteine to methionine and recycling the methyl group from methylfolate. Folate then can be converted into its coenzyme form, allowing for amino acid conversion reactions and the synthesis of nucleic acids, RNA and DNA [1].

Is my diet complete without cofactors?

We concern ourselves with the balance of nutrients we take in each day, not for their individual value in our bodies, but for the way they work together, synergistically, to keep our complex and powerful biological systems functioning. For example, oranges are healthy food. They are full of vitamin C, which is essential, and sugars that provide a substrate for cellular energy. But you can’t thrive on oranges alone; even if you ate a truckload every day. Your body needs balance. 

When a supplement includes cofactors, it is like making sure you get some lean protein and healthy fat onto the plate with your oranges. Cofactors balance a beneficial nutrient with other different, but complementary, nutrients to make sure whatever body system you are aiming to support also has the other elements it needs for those important biochemical reactions to work efficiently.

Which nutrients need cofactors?

Cofactors are a great reason to take a daily multivitamin. It turns out many vitamins and minerals work as cofactors for each other, working together to support each of their primary functions. For example, vitamin D is a popular nutrient to supplement with, due to lack of sun exposure. However, vitamin D has a number of cofactors, without which you won’t get all of the potential benefits that vitamin D has to offer. The most important cofactors for vitamin D are:

  • Magnesium
  • Vitamin K
  • Zinc
  • Boron
  • Vitamin A

While every organ in your body needs magnesium to function properly and participate in many biological processes, it also plays a role as a cofactor for the use of other important nutrients such as calcium, phosphorus, sodium, potassium, and vitamin D [2]. Unfortunately, the Vitamin D Council has reported that the daily amounts of magnesium recommended by the Food and Nutrition Board are likely too low, that both men and women may need more than is recommended, and that the majority of Americans are magnesium deficient [2]. Magnesium is required to activate vitamin D into a form your body can use and helps vitamin D to maintain calcium in the body for bone health.

Zinc and vitamin K work together with vitamin D to strengthen your bones and to help them develop properly. Zinc may also assist in vitamin D’s cellular activities. Boron is a trace mineral, meaning its presence in your body is only necessary in tiny amounts but is necessary for your health nonetheless. It aids in the use of minerals that are key to vitamin D’s function, such as calcium and magnesium, to keep your bones healthy, supports brain function, and affects the hormone levels in your body [2].

Vitamin A and vitamin D work in a delicate balance to carry out the functions prescribed by the genetic code. It is possible to have too much vitamin A, and so levels of these two supplements should be carefully considered with the support of a healthcare professional.

Are there supplements that include cofactors?

Yes! The more researchers learn about the cofactors needed to support the function of supplemental nutrients, the more nutritional health companies are able to supply products that contain everything you need for the maximum nutritional benefit from your supplement.

L-methylfolate is a great example. Metabolic Maintenance is now offering L-methylfolate in a range of dosing options PLUS cofactors. There has been a lot of media attention in the nutrition world around the central role of methylation in good health. For efficient methylation in all of our cells, and proper neurotransmitter production we need a minimum intake of folate (vitamin B-9). Unfortunately, about half of the population cannot process synthetic folic acid found in fortified foods and most supplements you’ll find at the grocery store. Supplementing instead with l-methylfolate, the activated form of folate, allows your body to use the nutrient immediately, skipping the processing step that many of our systems struggle with.

Again, however, l-methylfolate does not work alone in your cells. It needs a number of cofactors present at adequate levels to do its job. The most important cofactors for folate (provided by the L-methylfolate Plus Cofactors formula) are B-6 and B-12. 

Homocysteine levels can build up in the blood without vitamin B-6, as B-6 aids in glutathione synthesis using homocysteine[3]. B-12 deficiency can also halt the same cycle, but by preventing homocysteine from being converted to methionine. L-methylfolate and B-12 are essentially coenzymes in the folate methylation process. More specifically, the primary remethylation pathway is catalyzed by methionine synthase with the help of vitamin B-12 and activated folic acid (L-methylfolate) [3].

Magnesium has also been added to this formula as it is a cofactor in more than 325 enzymatic reactions and about two-thirds of the American population are estimated to be magnesium deficient [4]. Magnesium is a cofactor for the COMT enzyme, which transfers a methyl group from SAMe to metabolize dopamine, norepinephrine, and epinephrine [4]. Many people who have experienced folate deficiency due to genetic mutations have also experienced the downstream symptoms of mood imbalance from insufficient or dysregulated neurotransmitter synthesis. Once the methylation cycle is stabilized with supplementation, adequate magnesium levels become more important as the body and brain need to process the upregulation of neurotransmitters being created [4].

SAMe is another nutritional supplement that Metabolic Maintenance now offered with cofactors. SAMe is another critical player in methylation, participating in several important reactions, including the formation of healthy levels of neurotransmitters. Because of this function, SAMe has been extensively researched for its ability to promote positive mood and emotional balance [5]. SAMe has been shown to promote joint comfort, in part by helping to reduce inflammation and support connective tissue strength [5]. Methylation is also an important Phase II detox pathway. SAMe has been shown to improve liver function as measured by standard liver tests and to increase hepatic glutathione levels [5].

As cofactors for the methylation cycle, folate, B-6, and B-12 are all required in order to reap the benefits from SAMe. Therefore, they have all been included in this SAMe Plus Cofactors formula, in their most bioavailable forms, along with magnesium, again as a cofactor for neurotransmitter synthesis and transmission.

Keep your supplements just as balanced as your healthy diet by staying sharp on your cofactor knowledge. Talk to your trusted healthcare professional about the nutritional support system that will maximize the benefits of each vitamin and mineral in your diet.

DIM is another product that Metabolic Maintenance offers with cofactors. Diindolylmethane (or DIM) is both an antioxidant and phytonutrient. It is a natural substance generated when acids in the stomach break down indole-3-carbinol (I3C), a compound found in cruciferous vegetables. Unfortunately, you would have to eat two pounds of kale, brussels sprouts, or broccoli in order to consume the daily recommended intake of DIM. 

DIM is a regulator of estrogen metabolism, as it promotes both breakdown and synthesis of estrogen in the body. Levels of total estrogen in the body are less important than the forms in which the hormone is present. The estrogen metabolites produced when DIM is active are known as 2-OH estrogens and have a severely less-pronounced estrogenic effect than the 16-OH estrogens and 4-OH estrogens that can cause inflammation, uncontrolled cellular mutation, and over-proliferation of cells (pathways associated with chronic pain and cancer growth) [6,7]. DIM has been shown to reduce estrogen receptor activity, promote healthy estrogen metabolite production, and support selective apoptosis, which helps to flush out damaged cells from the body. 

We often associate estrogen with women only, but DIM is beneficial to both men and women. As men age, their levels of testosterone naturally decline, while the activity of the enzyme that converts testosterone into estrogen called “aromatase” increases. The overall effect is an increase in estrogenic influence. DIM suppresses the ability of aromatase to convert testosterone to estradiol, thereby increasing the availability of free testosterone in the system. DIM supplementation can promote a natural elevation in testosterone and prostate health in men [8]. 

Some estrogen-like chemicals found in herbicides, pesticides, or emitted from plastics (such as phthalates and phenols like Bisphenol A) can also have an estrogen-like or “xenoestrogenic” effect in the body; and in some cases they are carcinogenic. These chemicals bind to estrogen receptors and wreak havoc on hormonal balance in both men and women. The anti-inflammatory estrogen metabolites produced by DIM may help to flush these estrogen-mimics to support the body’s return to hormonal balance.

Vitamin E, vitamin C, N-acetyl cysteine (NAC), and lemon bioflavonoids are added to this formula with DIM as they are also powerful antioxidants that participate in the oxidation of estrogen metabolites. The B vitamins that act as cofactors in the relevant biological processes for DIM’s action are methylfolate, B-12 (methylcobalamin), and B-6. These vitamins all play important roles in estrogen detoxification through methylation. Calcium-D-glucarate also aids in detoxification, as it binds with estrogen to facilitate its elimination from the body. 

Calcium-D-glucarate has been shown to inhibit beta-glucuronidase, an enzyme involved in Phase II liver detoxification. While that may sound negative, elevated beta-glucuronidase activity is associated with an increased risk for various cancers, particularly hormone-dependent cancers such as breast, prostate, and colon cancers [9]. Calcium-D-glucarate’s inhibition of beta-glucuronidase activity allows the body to excrete estrogen metabolites before they can become reabsorbed. The other cofactors aid in the processes involved in that excretion and hormonal detoxification.


  1. Freeland-Graves, J.H. and C. Bavik, “COENZYMES” Encyclopedia of Food Sciences and Nutrition (Second Edition), 2003
  2. Vitamin D Council. “Vitamin D and other vitamins and minerals.” copyright 2019.
  3. Audhya, Tapan. “Role of B Vitamins in Biological Methylation.” Health Diagnostics and Research Institute (2012): 1-20.
  4. Greenblatt, James.” Magnesium: The Missing Link in Mental Health.” Integrated Medicine for Mental Health. November 17, 2016. “
  5. Metabolic Maintenance. “SAMe Plus Cofactors”. Product Details. Accessed July 31, 2019.–Cofactors/
  6. Chen, I, McDougal A, Wang F, Safe S; Aryl hydrocarbon receptor-mediated anti-estrogenic and anti-tumorigenic activity of diindolylmethane (DIM). Carcinogenesis 1998 Sep; 19(9): 1631-9.
  7. Dalessandri KM, Firestone GL, Fitch MD, Bradlow HL, Bjeldanes LF. Pilot study: effect of 3,3′-diindolylmethane supplements on urinary hormone metabolites in postmenopausal women with a history of early-stage breast cancer. Nutr Cancer. 2004;50(2):161-7.
  8. Heath, Elisabeth I., et al. “A phase I dose-escalation study of oral BR-DIM (BioResponse 3, 3′-Diindolylmethane) in castrate-resistant, non-metastatic prostate cancer.” American journal of translational research 2.4 (2010): 402.
  9. Walaszek, Zbigniew, et al. “Metabolism, uptake, and excretion of a D-glucaric acid salt and its potential use in cancer prevention.” Cancer detection and prevention 21.2 (1997): 178-190.